Macrocyclic azolopyridine derivatives as eed and prc2 modulators

ABSTRACT

The invention relates to modulators of Embryonic Ectoderm Development (EED) and/or Polycomb Repressive Complex 2 (PRC2) useful in the treatment of disorders and diseases associated with EEC and PRC2, being macrocyclic azolopyridine derivatives and compositions thereof of Formula I:or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, or tautomer thereof, wherein X1, X2, X3, A1, A2, Y, R1, R2, R3, and R4 are as described herein.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/858,404, filed Apr. 24, 2020, which is a continuation ofInternational Patent Application No. PCT/US2020/022724, filed Mar. 13,2020, which claims the benefit of, and priority to, U.S. ProvisionalPatent Application No. 62/819,064, filed on Mar. 15, 2019, the entirecontents of each of which are incorporated by reference in theirentireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The present application contains a Sequence Listing, which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 11, 2020, isnamed “FULC-034-01WO_SeqList.txt” and is 6 KB in size.

FIELD OF INVENTION

The present disclosure relates to macrocyclic azolopyridine derivatives,compositions comprising these compounds, methods of treating diseases ordisorders associated with Embryonic Ectoderm Development (EED) and/orPolycomb Repressive Complex 2 (PRC2), e.g., by modulating geneexpression, and methods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

Polycomb group (PcG) proteins are a family of chromatin modifyingenzymes that play a key role in gene expression and are dysregulated inmany human diseases. The PcG family includes two classes of PolycombRepressive Complexes (PRCs), namely Polycomb Repressive Complex 1 (PRC1)and Polycomb Repressive Complex 2 (PRC2). PRC2 includes SUZ12(suppressor of zeste 12), EED (embryonic ectoderm development) and thecatalytic subunit, EZH2 (enhancer of zeste homolog 2), and repressesgenes by methylating histone H3 lysine 27 (H3K27me3) at and around thepromoter regions of genes. This critical component of chromatinregulation is involved in modulation of gene transcription and playscrucial function in development, differentiation, and regeneration.Although EZH2 is the catalytic subunit, PRC2 minimally requires EED andSUZ12 for its methyltransferase activity. EED, SUZ12 and EZH2 have beenfound to be overexpressed in many cancers, which include but are notlimited to hepatocellular carcinoma, breast cancer, prostate cancer,etc. Activating mutations in EZH2 have been found in FL (follicularlymphoma) and DLBCL (diffuse large B cell lymphoma) patients. EEDnormally mediates repression of gene activity by binding to di- andtrimethylated lysine 27 of histone 3 where it allosterically activatesEZH2 activity of PRC2. EED has also been reported to recruit PRC1 toH3K27me3 loci and to enhance PRC1 mediated H2A ubiquitin E3 ligaseactivity.

Taken together, EED is a critical regulator of PRC2 in the silencing ofexpression of genes and gene clusters involved in development includingbut not limited to fetal orthologues (i.e. gamma globin), Hox genes, Xchromosome inactivation, etc. Thus, EED provides a pharmacologic targetfor the treatment of diseases or disorders to impact transcription ofspecific target genes in blood and other tissues. The need exists forsmall molecules that modulate EED and/or PRC2.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers, isomers, and tautomers thereof,wherein:

X₁, X₂, and X₃ are independently N or C(R₅), provided that X₁, X₂, andX₃ are not all N and at least one of X₁, X₂, or X₃ is N;

A₁ is a bond, —C(R₈)(R₉)—, —O—, —NR₈, —S—, —S(O)—, or —SO₂—;

A₂ and Y are independently at each occurrence —C(R₈)(R₉)—, —O—, —NR₈,—S—, —S(O)—, or —SO₂—;

R₁ is H, halogen, —NR₈R₉, —P(O)(OR₈)(OR₉), —C(O)R₈, —C(O)NR₈R₉, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆;

R₂ and R₃ are independently at each occurrence H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇;

R₄ is H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇,

or R₄ and R₉ when taken together can form C₃-C₁₀ cycloalkyl, C₅-C₈cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl,cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₁₀;

R₅ is H, halogen, —CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈cycloalkenyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₇;

R₆ is independently at each occurrence oxo, halogen, —CN, OH, —NR₈R₉,—OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₁₀; or

two R₆ can combine to form C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₀;

R₇ is independently at each occurrence oxo, halogen, —CN, —OR₈, —C(O)R₈,—C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉,—S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R₈ is independently at each occurrence H, OH, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₁₀;

R₉ is independently at each occurrence H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₁₀;

or R₈ and R₉ when taken together form a C₃-C₆ cycloalkyl orheterocyclyl, wherein the cycloalkyl or heterocyclyl is optionallysubstituted with R₁₀; and

R₁₀ is independently at each occurrence oxo, halogen, —CN, —OR₁₁,—C(O)R₁₁, —C(O)OR₁₁, —C(O)NR₁₁R₁₂, —NR₁₁R₁₂, —NR₁₁C(O)R₁₂, —S(O)R₁₁,—S(O)₂R₁₁, —NR₁₁S(O)₂R₁₂, —S(O)₂NR₁₁R₁₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl; and

R₁₁ and R₁₂ are independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier may further include anexcipient, diluent, or surfactant.

Another aspect of the invention is directed to a method of treating adisease or disorder associated with modulation of embryonic ectodermdevelopment (EED). The method involves administering to a patient inneed thereof an effective amount of the compound of Formula I.

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of Polycomb RepressiveComplex 2 (PRC2). The method comprises administering to a patient inneed thereof an effective amount of the compound of Formula I.

The present invention further provides methods of treating a cancerselected from diffused large B cell lymphoma, follicular lymphoma, otherlymphomas, leukemia, multiple myeloma, mesothelioma, gastric cancer,malignant rhabdoid tumor, hepatocellular carcinoma, prostate cancer,breast carcinoma, bile duct and gallbladder cancers, bladder carcinoma,brain tumors including neuroblastoma, schwannoma, glioma, glioblastomaand astrocytoma, cervical cancer, colon cancer, melanoma, endometrialcancer, esophageal cancer, head and neck cancer, lung cancer,nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal cellcarcinoma, rectal cancer, thyroid cancers, parathyroid tumors, uterinetumors, and soft tissue sarcomas.

The present invention further provides methods of a blood disorderselected from Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia(AML) (e.g., acute promyelocytic leukemia, APL), Amyloidosis, Anemia,Aplastic anemia, Bone marrow failure syndromes, Chronic lymphocyticleukemia (CLL), Chronic myeloid leukemia (CML), Deep vein thrombosis(DVT), Diamond-Blackfan anemia, Dyskeratosis congenita (DKC),Eosinophilic disorder, Essential thrombocythemia, Fanconi anemia,Gaucher disease, Hemochromatosis, Hemolytic anemia, Hemophilia,Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathicthrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes,Iron-deficiency anemia, Langerhans cell histiocytosis, Large granularlymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis,Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes(MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin'slymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia(B12 deficiency), Polycythemia vera, Porphyria, Post-transplantlymphoproliferative disorder (PTLD), Pulmonary embolism (PE),Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD), Thalassemia(e.g., β-thalassemia), Thrombocytopenia, Thrombotic thrombocytopenicpurpura (TTP), Venous thromboembolism, Von Willebrand disease, andWaldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma).

The present invention further provides methods of treating sickle celldisease (SCD) or β-thalassemia. The method comprises administering to apatient in need thereof an effective amount of the compound of FormulaI.

The present invention further provides methods of treating thoracicaortic aneurysm, coronary heart disease, stenotic disease, pulmonaryartery hypertension (PAH), liver fibrosis, allergic inflammation,retinitis pigmentosa, septic shock, herpes simplex virus, humancytomegalovirus, α-thalassemia, familial atrial fibrillation, commonvariable immunodeficiency, aneurysm-osteoarthritis syndrome, andacquired immunodeficiency syndrome. The method comprises administeringto a patient in need thereof an effective amount of the compound ofFormula I.

The present invention further provides use of a compound of Formula Ifor treating a disease or disorder associated with the modulation ofembryonic ectoderm development (EED).

The present invention further provides use of a compound of Formula Ifor treating a disease or disorder associated with the modulation ofPolycomb Repressive Complex 2 (PRC2).

The present invention further provides a compound of Formula I for usein the manufacture of a medicament for treating a disorder or diseaseassociated with embryonic ectoderm development (EED).

The present invention further provides a compound of Formula I for usein the manufacture of a medicament for treating a disorder or diseaseassociated with Polycomb Repressive Complex 2 (PRC2).

DETAILED DESCRIPTION OF THE INVENTION

EED mediates repression of gene activity by binding to di- andtrimethylated lysine 27 of histone 3 where it allosterically activatesthe methyltransferase activity of PRC2, functions to recruit PRC1 toH3K27me3 loci, enhances PRC1 mediated H2A ubiquitin E3 ligase activityand regulates PRC2 in the silencing of expression of genes and geneclusters involved in development, i.e., Hox genes, and in X chromosomeinactivation. Thus, EED and/or PRC2 provides a pharmacological targetfor the diseases or disorders, including cancers, to impacttranscription.

Hemoglobin is the critical protein involved in oxygen transportthroughout the body of vertebrates. It is found in red blood cells andconsists of two a subunits and two 3 subunits. The composition ofhemoglobin is developmentally regulated where the human genome encodesmultiple versions of these proteins that are expressed during distinctstages of development (Blobel et al., Exp. Hematol. 2015, incorporatedherein by reference; Stamatoyannopoulos G, Exp. Hematol. 2005,incorporated herein by reference). In general, fetal hemoglobin (HbF) iscomposed of two subunits of hemoglobin γ (HBγ) and two subunits ofhemoglobin α (HBα) and adult hemoglobin (HbA) is composed of twosubunits of hemoglobin β (HBβ) and two subunits of HBα. Thus, the βsubunit utilized during the fetal stage of development is (HBγ) andswitches to hemoglobin β (HBβ) after birth. Red blood cell disorderslike sickle cell disease (SCD) and β-thalassemias are caused byalterations within the gene for the hemoglobin β (HBβ) subunit. SCD isan autosomal recessive disease caused by a single mutation in bothcopies of the HBB gene (E6V). A fetal ortholog of HBβ, hemoglobin γ(HBγ) can reverse disease-related pathophysiology in these disorders byalso forming complexes with the required hemoglobin α subunit (Paikariand Sheehan, Br. J. Haematol. 2018, incorporated herein by reference;Lettre and Bauer, Lancet 2016, incorporated herein by reference).Because β-like globin expression is developmentally regulated, with areduction in the fetal ortholog (γ) occurring shortly after birthconcomitantly with an increase in the adult ortholog (β), it has beenpostulated that maintaining expression of the anti-sickling γ orthologmay be of therapeutic benefit in children and adults.

The developmental regulation of the expression of β-like subunits hasbeen the focus of intense studies for decades (Li et al. Blood 2002,incorporated herein by reference). All five β-like subunits in humansreside on chromosome 11 where their genomic location corresponds totheir temporal expression pattern. A distal cluster of enhancerelements, called the locus control region (LCR), coordinates theexpression pattern at the β globin locus where multiple transcriptionfactors including GATA1, GATA2, KLF1, KLF2, and MYB and TAL1 bind atspecific locations within the LCR at specific times in development. Thefive human β-like subunits are epsilon (HBE1; ε), gammaG (HBG2; γ),gammaA (HBG1; γ), delta (HBD; δ) and beta (HBB; β). HBE1 is expressedduring embryonic development, HBG1 and HBG2 are expressed during fetaldevelopment, and HBD and HBB are expressed in adults. The HBG1 and HBG2genes encode identical proteins except for a single amino acid change atresidue 136 (HBG1=gly; HBG2=ala). Functionally, however, upregulation ofeither gene can compensate for mutant or defect adult HBβ.

Sickle cell disease (SCD) is caused by homozygous mutations in the HBBgene product (E6V) that results in a mutant hemoglobin protein (HbS).Under deoxygenated conditions, the HbS protein polymerizes which leadsto abnormal red blood cell morphology. This abnormal morphology can leadto multiple pathologic symptoms including vaso-occlusion, pain crises,pulmonary hypertension, organ damage, and stroke. Expression of thefetal hemoglobin protein can reverse the SCD pathophysiology throughinhibiting HbS polymerization and morphologically defective red bloodcells. SCD affects millions of people worldwide and is the most commoninherited blood disorder in the United States (70,000-80,000 Americans).SCD has a high incidence in African Americans where it is estimated tooccur in 1 in 500 individuals. β-thalassemia is caused by mutations inthe HBB gene and is the result of reduced hemoglobin production. Themutations in the HBB gene typically reduce the production of adultβ-globin protein which leads to low levels of adult hemoglobin, HbA.This leads to a shortage of red blood cells and a lack of oxygendistribution throughout the body. Patients with β-thalassemias can haveweakness, fatigue and are at risk of developing abnormal blood clots.Thousands of infants are born with β-thalassemia each year wheresymptoms are typically detected within the first two years of life. Theidentification of factors that regulate the expression of fetalhemoglobin could be useful targets for the treatment of SCD andβ-thalassemias as upregulation of fetal hemoglobin could compensate formutant HbS protein in SCD or a lack of HbA in β-thalassemias.

Based on clinical and preclinical studies, upregulation of hemoglobin γ(HBγ) is the proposed mechanism for compounds including Palmolidomideand Hydroxyurea and targets including EHMT1/EHMT2 and LSD1 (Moutouh-deParseval et al. J. Clin. Invest. 2008, incorporated herein by reference;Letvin et al. NEJM 1984, incorporated herein by reference; Renneville etal. Blood 2015, incorporated herein by reference; Shi et al. Nature Med.2015, incorporated herein by reference). We discovered that treatmentwith inhibitors of Polycomb Repressive Complex 2 (PRC2) function throughtargeting the EED subunit leads to HBγ upregulation.

The PRC2 complex is an evolutionarily conserved multi-subunit chromatinregulatory complex that functions in repression of gene expression(Margueron and Reinberg, Nature 2011, incorporated herein by reference).The four core PRC2 subunits are EED, SUZ12, RbAp48 and EZH1 or EZH2.EZH1 and EZH2 contain methyltransferase activity and catalyzetrimethylation of lysine 27 on histone H3 (H3K27me3). The EED subunitcan bind to the H3K27me3 mark and stimulate EZH2 methyltransferaseactivity. Additional subunits can associate with PRC2 that may impactcomplex localization on chromatin in specific regions of the genomewhich leads to the formation of H3K27me3-marked chromatin domains. Thedeposition of the H3K27me3 modification is typically associated with therepression of gene expression.

The present invention provides, inter alia, modulators of EED and/orPRC2, and prophylactic measures to treat diseases and disordersassociated with EED and/or PRC2.

In a first aspect, the invention provides compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers, isomers, and tautomers thereof, wherein X₁, X₂, X₃, A₁, A₂,Y, R₁, R₂, R₃, and R₄ are as described above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded to other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, CN, —COOH, —CH₂CN, —O—C₁-C₆alkyl, C₁-C₆ alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C₂-C₆ alkenyl,—C₂-C₆ alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl,—OC(O)OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, —NHC(O)C₁-C₆alkyl, —C(O)NHC₁-C₆ alkyl, —S(O)₂—C₁-C₆ alkyl, —S(O)NHC₁-C₆ alkyl, andS(O)N(C₁-C₆ alkyl)₂.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—C₁-C₆ alkyl, C₁-C₆ alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl,—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl,—C(O)C₁-C₆ alkyl, —OC(O)OC₁-C₆ alkyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆alkyl)₂, —S(O)₂—C₁-C₆ alkyl, —S(O)NHC₁-C₆ alkyl, and S(O)N(C₁-C₆alkyl)₂. The substituents can themselves be optionally substituted.Furthermore when containing two fused rings the aryl groups hereindefined may have an unsaturated or partially saturated ring fused with afully saturated ring. Exemplary ring systems of these aryl groupsinclude indanyl, indenyl, tetrahydronaphthalenyl, andtetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 10 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, or S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, or S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl,and derivatives thereof. Furthermore when containing two fused rings thearyl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a C₁-C₆ alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain.Examples of alkoxy groups include without limitation, methoxy, ethoxy,propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. Examples of alkenyl groups include ethenyl,propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

“Cycloalkyl” means monocyclic or bicyclic saturated carbon ringscontaining 3-18 carbon atoms. Examples of cycloalkyl groups include,without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentyl, or bicyclo[2.2.2]octenyl.

“Heterocyclyl” or “heterocycloalkyl” means a monocyclic or polycyclicradical of 3 to 24-membered ring containing carbon and heteroatoms takenfrom containing one or more ring heteroatoms selected from N, O, S, P,or B and wherein there is not delocalized % electrons (aromaticity)shared among the ring carbon or heteroatoms. Heterocyclyl rings include,but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, andhomotropanyl. In accordance with the present invention, heterocyclylrefers to saturated or partially saturated non aromatic rings structuresin which there is at least one heteroatoms selected from the group N, O,or S. In some embodiments, the one or more heteroatoms in theheterocyclyl are presented at an oxidated state

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₅-C₁₂)spirocycloalkyl is a spirocycle containing between 5 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the atoms in one of the ringsis a heteroatom. In some embodiments, at least one of the atoms in oneof the rings is O, N, S, or P.

The term “oxo” as used herein refers to an “═O” group.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric atom and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers. The term stereoisomer may alsoencompass atropisomers, which arise from hindered rotation about asingle bond, e.g., in compounds having a substituted biphenyl moiety.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

In one embodiment, X₁ is N or C(R₅). In one embodiment, X₁ is N. In oneembodiment, X₁ is C(R₅). In one embodiment, X₂ is N. In one embodiment,X₂ is C(R₅). In one embodiment, X₃ is N. In one embodiment, X₃ is C(R₅).

In one embodiment, A₁ is a bond, —C(R₈)(R₉)—, —O—, —NR₈—, —S—, —S(O)—,or —SO₂—.

In one embodiment, A₂ and Y are independently at each occurrence—C(R₈)(R₉)—, —O—, —NR₈—, or —SO₂—.

In one embodiment, A₁ is —C(R₈)(R₉)—, —O—, —NR₈—, —S—, —S(O)—, or—SO₂—In one embodiment, A₁ is a bond. In one embodiment, A₁ is—C(R₈)(R₉)— or —O—. In one embodiment, A₁ is —C(R₈)(R₉)—. In oneembodiment, A₁ is —O—. In one embodiment, A₁ is —NR₈—. In oneembodiment, A₁ is —S—. In one embodiment, A₁ is —S(O)—. In oneembodiment, A₁ is —SO₂—.

In one embodiment, A₂ is —C(R₈)(R₉)—, —O—, —NR₈—, or —SO₂—. In oneembodiment, A₂ is —C(R₈)(R₉)— or —O—. In one embodiment, A₂ is—C(R₈)(R₉)—. In one embodiment, A₂ is —O—. In one embodiment, A₂ is—NR₈—. In one embodiment, A₂ is —S—. In one embodiment, A₂ is —S(O)—. Inone embodiment, A₂ is —SO₂—.

In one embodiment, Y is —C(R₈)(R₉)—, —O—, —NR₈—, or —SO₂—In oneembodiment, Y is —C(R₈)(R₉)— or —O—. In one embodiment, Y is—C(R₈)(R₉)—. In one embodiment, Y is —O—. In one embodiment, Y is —NR₈—.In one embodiment, Y is —S—. In one embodiment, Y is —S(O)—. In oneembodiment, Y is —SO₂—.

In one embodiment, R₁ is H, halogen, —NR₈R₉, —P(O)(OR₈)(OR₉), —C(O)R₈,—C(O)NR₈R₉, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl. In one embodiment,R₁ is H. In one embodiment, R₁ is —NR₈R₉. In one embodiment, R₁ is—P(OR₈)(OR₉). In one embodiment, R₁ is —C(O)R₈. In one embodiment, R₁ is—C(O)NR₈R₉. In one embodiment, R₁ is —CN. In one embodiment, R₁ is C₁-C₆alkyl. In one embodiment, R₁ is C₁-C₆ alkoxy. In one embodiment, R₁ isC₂-C₆ alkenyl. In one embodiment, R₁ is C₂-C₆ alkynyl. In oneembodiment, R₁ is C₃-C₁₀ cycloalkyl. In one embodiment, R₁ is C₅-C₈cycloalkenyl. In one embodiment, R₁ is C₃-C₈ spirocycloalkyl. In oneembodiment, R₁ is spiroheterocyclyl. In one embodiment, R₁ isheterocyclyl. In one embodiment, R₁ is aryl. In one embodiment, R₁ isheteroaryl.

In one embodiment, R₁ is C₁-C₆ alkyl is optionally substituted with oneor more R₆. In one embodiment, R₁ is C₁-C₆ alkoxy is optionallysubstituted with one or more R₆. In one embodiment, R₁ is C₂-C₆ alkenylis optionally substituted with one or more R₆. In one embodiment, R₁ isC₂-C₆ alkynyl is optionally substituted with one or more R₆. In oneembodiment, R₁ is C₃-C₁₀ cycloalkyl is optionally substituted with oneor more R₆. In one embodiment, R₁ is C₅-C₈ cycloalkenyl is optionallysubstituted with one or more R₆. In one embodiment, R₁ is C₃-C₈spirocycloalkyl is optionally substituted with one or more R₆. In oneembodiment, R₁ is spiroheterocyclyl is optionally substituted with oneor more R₆. In one embodiment, R₁ is heterocyclyl is optionallysubstituted with one or more R₆. In one embodiment, R₁ is aryl isoptionally substituted with one or more R₆. In one embodiment, R₁ isheteroaryl is optionally substituted with one or more R₆.

In another embodiment, R₁ is

In another embodiment, R₁ is

In another embodiment, R₁ is

In another embodiment, R₁ is

In another embodiment, R₁ is

In one embodiment, R₁ is

In one embodiment, R₂ is independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl. In one embodiment, R₂ is H. In one embodiment, R₂ is halogen.In one embodiment, R₂ is —OH. In one embodiment, R₂ is —NH₂. In oneembodiment, R₂ is —CN. In one embodiment, R₂ is C₁-C₆ alkyl. In oneembodiment, R₂ is C₁-C₆ alkoxy. In one embodiment, R₂ is C₂-C₆ alkenyl.In one embodiment, R₂ is C₂-C₆ alkynyl.

In one embodiment, R₂ is C₁-C₆ alkyl optionally substituted with one ormore R₇. In one embodiment, R₂ is C₁-C₆ alkoxy optionally substitutedwith one or more R₇. In one embodiment, R₂ is C₂-C₆ alkenyl optionallysubstituted with one or more R₇. In one embodiment, R₂ is C₂-C₆ alkynyloptionally substituted with one or more R₇.

In one embodiment, R₃ is independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl. In one embodiment, R₃ is H. In one embodiment, R₃ is halogen.In one embodiment, R₃ is —OH. In one embodiment, R₃ is —NH₂. In oneembodiment, R₃ is —CN. In one embodiment, R₃ is C₁-C₆ alkyl. In oneembodiment, R₃ is C₁-C₆ alkoxy. In one embodiment, R₃ is C₂-C₆ alkenyl.In one embodiment, R₃ is C₂-C₆ alkynyl.

In one embodiment, R₃ is C₁-C₆ alkyl optionally substituted with one ormore R₇. In one embodiment, R₃ is C₁-C₆ alkoxy optionally substitutedwith one or more R₇. In one embodiment, R₃ is C₂-C₆ alkenyl optionallysubstituted with one or more R₇. In one embodiment, R₃ is C₂-C₆ alkynyloptionally substituted with one or more R₇.

In one embodiment, R₄ is independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl. In one embodiment, R₄ is H. In one embodiment, R₄ is halogen.In one embodiment, R₄ is —OH. In one embodiment, R₄ is —NH₂. In oneembodiment, R₄ is —CN. In one embodiment, R₄ is C₁-C₆ alkyl. In oneembodiment, R₄ is C₁-C₆ alkoxy. In one embodiment, R₄ is C₂-C₆ alkenyl.In one embodiment, R₄ is C₂-C₆ alkynyl.

In one embodiment, R₄ is C₁-C₆ alkyl optionally substituted with one ormore R₇. In one embodiment, R₄ is C₁-C₆ alkoxy optionally substitutedwith one or more R₇. In one embodiment, R₄ is C₂-C₆ alkenyl optionallysubstituted with one or more R₇. In one embodiment, R₄ is C₂-C₆ alkynyloptionally substituted with one or more R₇.

In one embodiment, R₄ and R₉ can form C₃-C₁₀ cycloalkyl, C₅-C₈cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, R₄and R₉ can form C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, cycloalkenyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₀.

In one embodiment, R₄ and R₉ can form C₃-C₁₀ cycloalkyl. In oneembodiment, R₄ and R₉ can form C₅-C₈ cycloalkenyl. In one embodiment, R₄and R₉ can form heterocyclyl. In one embodiment, R₄ and R₉ can formaryl. In one embodiment, R₄ and R₉ can form heteroaryl.

In one embodiment, R₄ and R₉ can form C₃-C₁₀ cycloalkyl optionallysubstituted with one or more R₁₀. In one embodiment, R₄ and R₉ can formC₅-C₈ cycloalkenyl optionally substituted with one or more R₁₀. In oneembodiment, R₄ and R₉ can form heterocyclyl optionally substituted withone or more R₁₀. In one embodiment, R₄ and R₉ can form aryl optionallysubstituted with one or more R₁₀. In one embodiment, R₄ and R₉ can formheteroaryl optionally substituted with one or more R₁₀.

In one embodiment, R₅ is H, halogen, —CN, —OR₈, —NR₈R₉, —C(O)R₈,—C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉,—S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₇.

In one embodiment, R₅ is H, halogen, —CN, —OR₈, —NR₈R₉, —C(O)R₈,—C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉,—S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl. In one embodiment, R₅ is H. In one embodiment, R₅ ishalogen. In one embodiment, R₅ is CN. In one embodiment, R₅ is —OR₈. Inone embodiment, R₅ is —NR₈R₉. In one embodiment, R₅ is —C(O)R₈. In oneembodiment, R₅ is —C(O)OR₈. In one embodiment, R₅ is —C(O)NR₈R₉. In oneembodiment, R₅ is —NR₈C(O)R₉. In one embodiment, R₅ is —S(O)R₈. In oneembodiment, R₅ is —S(O)₂R₈. In one embodiment, R₅ is —NR₈S(O)₂R₉. In oneembodiment, R₅ is —S(O)₂NR₈R₉. In one embodiment, R₅ is C₁-C₆ alkyl. Inone embodiment, R₅ is C₁-C₆ haloalkyl. In one embodiment, R₅ is C₂-C₆alkenyl. In one embodiment, R₅ is C₂-C₆ alkynyl. In one embodiment, R₅is C₃-C₁₀ cycloalkyl. In one embodiment, R₅ is C₅-C₈ cycloalkenyl. Inone embodiment, R₅ is heterocyclyl. In one embodiment, R₅ is aryl. Inone embodiment, R₅ is heteroaryl.

In one embodiment, R₅ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, orC₂-C₆ alkynyl.

In one embodiment, R₅ is C₁-C₆ alkyl. In one embodiment, R₅ is methyl.In one embodiment, R₅ is ethyl. In one embodiment, R₅ is propyl. In oneembodiment, R₅ is butyl. In one embodiment, R₅ is pentyl. In oneembodiment, R₅ is hexyl.

In one embodiment, R₅ is C₁-C₆ alkyl optionally substituted with one ormore R₇. In one embodiment, R₅ is methyl optionally substituted with oneor more R₇. In one embodiment, R₅ is ethyl optionally substituted withone or more R₇. In one embodiment, R₅ is propyl optionally substitutedwith one or more R₇. In one embodiment, R₅ is butyl optionallysubstituted with one or more R₇. In one embodiment, R₅ is pentyloptionally substituted with one or more R₇. In one embodiment, R₅ ishexyl optionally substituted with one or more R₇.

In one embodiment, R₅ is C₁-C₆ haloalkyl. In one embodiment, R₅ ishalomethyl. In one embodiment, R₅ is haloethyl. In one embodiment, R₅ ishalopropyl. In one embodiment, R₅ is halobutyl. In one embodiment, R₅ ishalopentyl. In one embodiment, R₅ is halohexyl.

In one embodiment, R₅ is C₂-C₆ alkenyl. In one embodiment, R₅ is C₂-C₆alkynyl.

In one embodiment, R₅ is C₂-C₆ alkenyl optionally substituted with oneor more R₇. In one embodiment, R₅ is C₂-C₆ alkynyl optionallysubstituted with one or more R₇.

In one embodiment, R₅ is C₃-C₁₀ cycloalkyl or C₅-C₈ cycloalkenyl.

In one embodiment, R₅ is C₃-C₁₀ cycloalkyl or C₅-C₈ cycloalkenyl,wherein the cycloalkyl or cycloalkenyl is optionally substituted withone or more R₇.

In one embodiment, R₅ is C₃-C₁₀ cycloalkyl. In one embodiment, R₅ ismonocyclic C₃-C₁₀ cycloalkyl. In one embodiment, R₅ is bicyclic C₃-C₁₀cycloalkyl. In one embodiment, R₅ is polycyclic C₃-C₁₀ cycloalkyl.

In one embodiment, R₅ is C₃-C₁₀ cycloalkyl optionally substituted withone or more R₇. In one embodiment, R₅ is monocyclic C₃-C₁₀ cycloalkyloptionally substituted with one or more R₇. In one embodiment, R₅ isbicyclic C₃-C₁₀ cycloalkyl optionally substituted with one or more R₇.In one embodiment, R₅ is polycyclic C₃-C₁₀ cycloalkyl optionallysubstituted with one or more R₇.

In one embodiment, R₅ is C₅-C₈ cycloalkenyl. In one embodiment, R₅ isheterocyclyl, aryl, or heteroaryl. In one embodiment, R₅ isheterocyclyl. In one embodiment, R₅ is aryl. In one embodiment, R₅ isphenyl.

In one embodiment, R₅ is C₅-C₈ cycloalkenyl optionally substituted withone or more R₇. In one embodiment, R₅ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₇. In one embodiment, R₅ is heterocyclyloptionally substituted with one or more R₇. In one embodiment, R₅ isaryl optionally substituted with one or more R₇. In one embodiment, R₅is phenyl optionally substituted with one or more R₇.

In one embodiment, R₅ is heteroaryl. In one embodiment, R₅ is pyridine.In one embodiment, R₅ is imidazolyl. In one embodiment, R₅ is pyrazolyl.In one embodiment, R₅ is pyrimidinyl.

In one embodiment, R₅ is heteroaryl optionally substituted with one ormore R₇. In one embodiment, R₅ is pyridine optionally substituted withone or more R₇. In one embodiment, R₅ is imidazolyl optionallysubstituted with one or more R₇. In one embodiment, R₅ is pyrazolyloptionally substituted with one or more R₇. In one embodiment, R₅ ispyrimidinyl optionally substituted with one or more R₇.

In one embodiment, R₅ is —CF₃. In one embodiment, R₅ is —CHF₂. In oneembodiment, R₅ is —CH₂F.

In one embodiment, R₆ is independently at each occurrence oxo, halogen,—CN, OH, —NR₈R₉, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉,—S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl. Inone embodiment, R₆ is oxo. In one embodiment, R₆ is halogen. In oneembodiment, R₆ is CN. In one embodiment, R₆ is OH. In one embodiment, R₆is —NR₈R₉. In one embodiment, R₆ is —OR₈. In one embodiment, R₆ is—NR₈R₉. In one embodiment, R₆ is —C(O)R₈. In one embodiment, R₆ is—C(O)OR₈. In one embodiment, R₆ is —C(O)NR₈R₉. In one embodiment, R₆ is—NR₈C(O)R₉. In one embodiment, R₆ is —S(O)R₈. In one embodiment, R₆ is—S(O)₂R₈. In one embodiment, R₆ is —NR₈S(O)₂R₉. In one embodiment, R₆ is—S(O)₂NR₈R₉. In one embodiment, R₆ is C₁-C₆ alkyl. In one embodiment, R₆is C₁-C₆ haloalkyl. In one embodiment, R₆ is C₂-C₆ alkenyl. In oneembodiment, R₆ is C₂-C₆ alkynyl. In one embodiment, R₆ is C₃-C₁₀cycloalkyl. In one embodiment, R₆ is C₅-C₈ cycloalkenyl. In oneembodiment, R₆ is heterocyclyl. In one embodiment, R₆ is aryl. In oneembodiment, R₆ is heteroaryl.

In one embodiment, R₆ is C₁-C₆ alkyl optionally substituted with one ormore R₁₀. In one embodiment, R₆ is C₁-C₆ haloalkyl optionallysubstituted with one or more R₁₀. In one embodiment, R₆ is C₂-C₆ alkenyloptionally substituted with one or more R₁₀. In one embodiment, R₆ isC₂-C₆ alkynyl optionally substituted with one or more R₁₀. In oneembodiment, R₆ is C₃-C₁₀ cycloalkyl optionally substituted with one ormore R₁₀. In one embodiment, R₆ is C₅-C₈ cycloalkenyl optionallysubstituted with one or more R₁₀. In one embodiment, R₆ is heterocyclyloptionally substituted with one or more R₁₀. In one embodiment, R₆ isaryl optionally substituted with one or more R₁₀. In one embodiment, R₆is heteroaryl optionally substituted with one or more R₁₀.

In another embodiment, two R₆ may combine to form C₃-C₁₀ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In anotherembodiment, two R₆ may combine to form C₃-C₁₀ cycloalkyl. In anotherembodiment, two R₆ may combine to form C₅-C₈ cycloalkenyl. In anotherembodiment, two R₆ may combine to form a heteroaryl. In anotherembodiment, two R₆ may combine to form a heterocyclyl. In anotherembodiment, two R₆ may combine to form an aryl. In another embodiment,two R₆ may combine to form C₃-C₁₀ cycloalkyl, wherein the cycloalkyl isoptionally substituted with one or more R₁₀. In another embodiment, twoR₆ may combine to form C₅-C₈ cycloalkenyl, wherein the cycloalkenyl isoptionally substituted with one or more R₁₀. In another embodiment, twoR₆ may combine to form a heteroaryl, wherein the heteroaryl isoptionally substituted with one or more R₁₀. In another embodiment, twoR₆ may combine to form a heterocyclyl, wherein the heterocyclyl isoptionally substituted with one or more R₁₀. In another embodiment, twoR₆ may combine to form an aryl wherein the aryl is optionallysubstituted with one or more R₁₀.

In one embodiment, R₇ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₇ is independently at each occurrence oxo, halogen,or —CN. In one embodiment, R₇ is oxo. In one embodiment, R₇ is halogen.In one embodiment, R₇ is F, Cl, Br, or I. In one embodiment, R₇ is F orCl. In one embodiment, R₇ is F. In one embodiment, R₇ is Cl. In oneembodiment, R₇ is —CN.

In one embodiment, R₇ is independently at each occurrence —OR₈, —C(O)R₈,—C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, or—S(O)₂NR₈R₉. In one embodiment, R₇ is —OR₈. In one embodiment, R₇ is—C(O)R₈. In one embodiment, R₇ is —C(O)OR₈. In one embodiment, R₇ is—C(O)NR₈R₉. In one embodiment, R₇ is —NR₈C(O)R₉. In one embodiment, R₇is —S(O)R₈. In one embodiment, R₇ is —S(O)₂R₈. In one embodiment, R₇ is—NR₈S(O)₂R₉. In one embodiment, R₇ is —S(O)₂NR₈R₉.

In one embodiment, R₇ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In one embodiment, R₇ is C₁-C₆ alkyl. In one embodiment, R₇ is methyl.In one embodiment, R₇ is ethyl. In one embodiment, R₇ is propyl. In oneembodiment, R₇ is butyl. In one embodiment, R₇ is pentyl. In oneembodiment, R₇ is hexyl.

In one embodiment, R₇ is C₁-C₆ haloalkyl. In one embodiment, R₇ ishalomethyl. In one embodiment, R₇ is haloethyl. In one embodiment, R₇ ishalopropyl. In one embodiment, R₇ is halobutyl. In one embodiment, R₇ ishalopentyl. In one embodiment, R₇ is halohexyl.

In one embodiment, R₇ is C₂-C₆ alkenyl. In one embodiment, R₇ is C₂-C₆alkynyl.

In one embodiment, R₇ is independently at each occurrence C₃-C₈cycloalkyl or heterocyclyl. In one embodiment, R₇ is C₃-C₈ cycloalkyl.In one embodiment, R₇ is heterocyclyl.

In one embodiment, R₇ is independently at each occurrence aryl orheteroaryl. In one embodiment, R₇ is aryl. In one embodiment, R₇ isheteroaryl.

In one embodiment, R₈ is independently at each occurrence H, OH,halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R₁₀.

In one embodiment, R₉ is independently at each occurrence H, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R₁₀.

In one embodiment, R₈ and R₉ are independently at each occurrence H,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₈ and R₉ are independently at each occurrence H.

In one embodiment, R₈ and R₉ are independently at each occurrence C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₈ and R₉ are independently at each occurrence C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₁₀.

In one embodiment, R₈ is independently at each occurrence H, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R₁₀.

In one embodiment, R₈ is independently at each occurrence H, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₈ is H.

In one embodiment, R₈ is halogen.

In one embodiment, R₈ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₈ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₁₀.

In one embodiment, R₈ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl or C₂-C₆ alkynyl.

In one embodiment, R₈ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each alkyl,alkoxy, alkenyl or alkynyl is optionally substituted with one or moreR₁₀.

In one embodiment, R₈ is C₁-C₆ alkyl. In one embodiment, R₈ is methyl.In one embodiment, R₈ is ethyl. In one embodiment, R₈ is propyl. In oneembodiment, R₈ is butyl. In one embodiment, R₈ is pentyl. In oneembodiment, R₈ is hexyl.

In one embodiment, R₈ is C₁-C₆ alkyl optionally substituted with one ormore R₁₀. In one embodiment, R₈ is methyl optionally substituted withone or more R₁₀. In one embodiment, R₈ is ethyl optionally substitutedwith one or more R₁₀. In one embodiment, R₈ is propyl optionallysubstituted with one or more R₁₀. In one embodiment, R₈ is butyloptionally substituted with one or more R₁₀. In one embodiment, R₈ ispentyl optionally substituted with one or more R₁₀. In one embodiment,R₈ is hexyl optionally substituted with one or more R₁₀.

In one embodiment, R₈ is C₁-C₆ alkoxy. In one embodiment, R₈ is methoxy.In one embodiment, R₈ is ethoxy. In one embodiment, R₈ is propoxy. Inone embodiment, R₈ is butoxy. In one embodiment, R₈ is pentoxy. In oneembodiment, R₈ is hexoxy.

In one embodiment, R₈ is C₁-C₆ alkoxy optionally substituted with one ormore R₁₀. In one embodiment, R₈ is methoxy optionally substituted withone or more R₁₀. In one embodiment, R₈ is ethoxy optionally substitutedwith one or more R₁₀. In one embodiment, R₈ is propoxy optionallysubstituted with one or more R₁₀. In one embodiment, R₈ is butoxyoptionally substituted with one or more R₁₀. In one embodiment, R₈ ispentoxy optionally substituted with one or more R₁₀. In one embodiment,R₈ is hexoxy optionally substituted with one or more R₁₀.

In one embodiment, R₈ is C₂-C₆ alkenyl. In one embodiment, R₈ is C₂-C₆alkynyl.

In one embodiment, R₈ is C₂-C₆ alkenyl optionally substituted with oneor more R₁₀. In one embodiment, R₈ is C₂-C₆ alkynyl optionallysubstituted with one or more R₁₀.

In one embodiment, R₈ is independently at each occurrence C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₈ is independently at each occurrence C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₁₀.

In one embodiment, R₈ is C₃-C₈ cycloalkyl. In one embodiment, R₈ isheterocyclyl. In one embodiment, R₈ is aryl. In one embodiment, R₈ isheteroaryl.

In one embodiment, R₈ is C₃-C₈ cycloalkyl optionally substituted withone or more R₁₀. In one embodiment, R₈ is heterocyclyl optionallysubstituted with one or more R₁₀. In one embodiment, R₈ is aryloptionally substituted with one or more R₁₀. In one embodiment, R₈ isheteroaryl optionally substituted with one or more R₁₀.

In one embodiment, R₉ is independently at each occurrence H, halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R₁₀.

In one embodiment, R₉ is independently at each occurrence H, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₉ is H.

In one embodiment, R₉ is halogen.

In one embodiment, R₉ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₉ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₁₀.

In one embodiment, R₉ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl or C₂-C₆ alkynyl.

In one embodiment, R₉ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein each alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₁₀.

In one embodiment, R₉ is C₁-C₆ alkyl. In one embodiment, R₉ is methyl.In one embodiment, R₉ is ethyl. In one embodiment, R₉ is propyl. In oneembodiment, R₉ is butyl. In one embodiment, R₉ is pentyl. In oneembodiment, R₉ is hexyl.

In one embodiment, R₉ is C₁-C₆ alkyl optionally substituted with one ormore R₁₀. In one embodiment, R₉ is methyl optionally substituted withone or more R₁₀. In one embodiment, R₉ is ethyl optionally substitutedwith one or more R₁₀. In one embodiment, R₉ is propyl optionallysubstituted with one or more R₁₀. In one embodiment, R₉ is butyloptionally substituted with one or more R₁₀. In one embodiment, R₉ ispentyl optionally substituted with one or more R₁₀. In one embodiment,R₉ is hexyl optionally substituted with one or more R₁₀.

In one embodiment, R₉ is C₁-C₆ alkoxy. In one embodiment, R₉ is methoxy.In one embodiment, R₉ is ethoxy. In one embodiment, R₉ is propoxy. Inone embodiment, R₉ is butoxy. In one embodiment, R₉ is pentoxy. In oneembodiment, R₉ is hexoxy.

In one embodiment, R₉ is C₁-C₆ alkoxy optionally substituted with one ormore R₁₀. In one embodiment, R₉ is methoxy optionally substituted withone or more R₁₀. In one embodiment, R₉ is ethoxy optionally substitutedwith one or more R₁₀. In one embodiment, R₉ is propoxy optionallysubstituted with one or more R₁₀. In one embodiment, R₉ is butoxyoptionally substituted with one or more R₁₀. In one embodiment, R₉ ispentoxy optionally substituted with one or more R₁₀. In one embodiment,R₉ is hexoxy optionally substituted with one or more R₁₀.

In one embodiment, R₉ is C₂-C₆ alkenyl. In one embodiment, R₉ is C₂-C₆alkynyl.

In one embodiment, R₉ is C₂-C₆ alkenyl optionally substituted with oneor more R₁₀. In one embodiment, R₉ is C₂-C₆ alkynyl optionallysubstituted with one or more R₁₀.

In one embodiment, R₉ is independently at each occurrence C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₉ is independently at each occurrence C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₀.

In one embodiment, R₉ is C₃-C₈ cycloalkyl. In one embodiment, R₉ isheterocyclyl. In one embodiment, R₉ is aryl. In one embodiment, R₉ isheteroaryl.

In one embodiment, R₉ is C₃-C₈ cycloalkyl optionally substituted withone or more R₁₀. In one embodiment, R₉ is heterocyclyl optionallysubstituted with one or more R₁₀. In one embodiment, R₉ is aryloptionally substituted with one or more R₁₀. In one embodiment, R₉ isheteroaryl optionally substituted with one or more R₁₀.

In one embodiment, R₈ and R₉ when taken together form a C₃-C₆ cycloalkylor heterocycle, wherein the cycloalkyl or heterocycle is optionallysubstituted with R₁₀.

In one embodiment, R₈ and R₉ when taken together form a C₃-C₆cycloalkyl, wherein the cycloalkyl is optionally substituted with R₁₀.In one embodiment, R₈ and R₉ when taken together form a C₃-C₆cycloalkyl. In one embodiment, R₈ and R₉ when taken together formcyclopropyl, wherein the cyclopropyl is optionally substituted with R₁₀.In one embodiment, R₈ and R₉ when taken together form cyclopropyl.

In one embodiment, R₈ and R₉ when taken together form a heterocycle,wherein the heterocycle is optionally substituted with R₁₀. In oneembodiment, R₈ and R₉ when taken together form a 4-membered heterocycleoptionally substituted with R₁₀. In one embodiment, R₈ and R₉ when takentogether form azetidinyl optionally substituted with R₁₀. In oneembodiment, R₈ and R₉ when taken together form oxetanyl optionallysubstituted with R₁₀.

In one embodiment, R₁₀ is independently at each occurrence oxo, halogen,—CN, —OR₁₁, —C(O)R₁₁, —C(O)OR₁₁, —C(O)NR₁₁R₁₂, —NR₁₁C(O)R₁₂, —S(O)R₁₁,—S(O)₂R₁₁, —NR₁₁S(O)₂R₁₂, —S(O)₂NR₁₁R₁₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, R₁₀ is independently at each occurrence oxo, halogen,—CN, —OR₁₁, —C(O)R₁₁, —C(O)OR₁₁, —C(O)NR₁₁R₁₂, —NR₁₁R₁₂, —NR₁₁C(O)R₁₂,—S(O)R₁₁, —S(O)₂R₁₁, —NR₁₁S(O)₂R₁₂, —S(O)₂NR₁₁R₁₂, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl.

In one embodiment, R₁₀ is independently at each occurrence oxo, halogen,or —CN. In one embodiment, R₁₀ is oxo. In one embodiment, R₁₀ ishalogen. In one embodiment, R₁₀ is F, Cl, Br, or I. In one embodiment,R₁₀ is F or Cl. In one embodiment, R₁₀ is F. In one embodiment, R₁₀ isCl. In one embodiment, R₁₀ is —CN.

In one embodiment, R₁₀ is independently at each occurrence —OR₁₁,—C(O)R₁₁, —C(O)OR₁₁, —C(O)NR₁₁R₁₂, —NR₁₁C(O)R₁₂, —S(O)R₁₁, —S(O)₂R₁₁,—NR₁₁S(O)₂R₁₂, or —S(O)₂NR₁₁R₁₂. In one embodiment, R₁₀ is —OR₁₁. In oneembodiment, R₁₀ is —C(O)Rn. In one embodiment, R₁₀ is —C(O)OR₁₁. In oneembodiment, R₁₀ is —C(O)NR₁₁R₁₂. In one embodiment, R₁₀ is —NR₁₁C(O)R₁₂.In one embodiment, R₁₀ is —S(O)R₁₁. In one embodiment, R₁₀ is —S(O)₂R₁₁.In one embodiment, R₁₀ is —NR₁₁S(O)₂R₁₂. In one embodiment, R₁₀ is—S(O)₂NR₁₁R₁₂.

In one embodiment, R₁₀ is independently at each occurrence C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl.

In one embodiment, R₁₀ is C₁-C₆ alkyl. In one embodiment, R₁₀ is methyl.In one embodiment, R₁₀ is ethyl. In one embodiment, R₁₀ is propyl. Inone embodiment, R₁₀ is butyl. In one embodiment, R₁₀ is pentyl. In oneembodiment, R₁₀ is hexyl.

In one embodiment, R₁₀ is C₁-C₆ haloalkyl. In one embodiment, R₁₀ ishalomethyl. In one embodiment, R₁₀ is haloethyl. In one embodiment, R₁₀is halopropyl. In one embodiment, R₁₀ is halobutyl. In one embodiment,R₁₀ is halopentyl. In one embodiment, R₁₀ is halohexyl.

In one embodiment, R₁₀ is C₂-C₆ alkenyl. In one embodiment, R₁₀ is C₂-C₆alkynyl.

In one embodiment, R₁₀ is independently at each occurrence C₃-C₈cycloalkyl or heterocyclyl. In one embodiment, R₁₀ is C₃-C₈ cycloalkyl.In one embodiment, R₁₀ is heterocyclyl.

In one embodiment, R₁₀ is independently at each occurrence aryl orheteroaryl. In one embodiment, R₁₀ is aryl. In one embodiment, R₁₀ isheteroaryl.

In one embodiment, R₁₀ is —OH.

In one embodiment, R₁₁ and R₁₂ are independently H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl.

In one embodiment, R₁₁ and R₁₂ are independently H.

In one embodiment, R₁₁ and R₁₂ are independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl.

In one embodiment, R₁₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, R₁₁ is H.

In one embodiment, R₁₁ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₁₁ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,or C₂-C₆ alkynyl.

In one embodiment, R₁₁ is C₁-C₆ alkyl. In one embodiment, R₁₁ is methyl.In one embodiment, R₁₁ is ethyl. In one embodiment, R₁₁ is propyl. Inone embodiment, R₁₁ is butyl. In one embodiment, R₁₁ is pentyl. In oneembodiment, R₁₁ is hexyl.

In one embodiment, R₁₁ is C₁-C₆ haloalkyl. In one embodiment, R₁₁ ishalomethyl. In one embodiment, R₁₁ is haloethyl. In one embodiment, R₁₁is halopropyl. In one embodiment, Rn is halobutyl. In one embodiment,R₁₁ is halopentyl. In one embodiment, R₁₁ is halohexyl.

In one embodiment, R₁₁ is C₂-C₆ alkenyl. In one embodiment, R₁₁ is C₂-C₆alkynyl.

In one embodiment, R₁₁ is C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl. In one embodiment, R₁₁ is C₃-C₈ cycloalkyl. In oneembodiment, R₁₁ is heterocyclyl. In one embodiment, R₁₁ is aryl. In oneembodiment, R₁₁ is heteroaryl.

In one embodiment, R₁₂ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, R₁₂ is H.

In one embodiment, R₁₂ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, R₁₂ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl,or C₂-C₆ alkynyl.

In one embodiment, R₁₂ is C₁-C₆ alkyl. In one embodiment, R₁₂ is methyl.In one embodiment, R₁₂ is ethyl. In one embodiment, R₁₂ is propyl. Inone embodiment, R₁₂ is butyl. In one embodiment, R₁₂ is pentyl. In oneembodiment, R₁₂ is hexyl.

In one embodiment, R₁₂ is C₁-C₆ haloalkyl. In one embodiment, R₁₂ ishalomethyl. In one embodiment, R₁₂ is haloethyl. In one embodiment, R₁₂is halopropyl. In one embodiment, R₁₂ is halobutyl. In one embodiment,R₁₂ is halopentyl. In one embodiment, R₁₂ is halohexyl.

In one embodiment, R₁₂ is C₂-C₆ alkenyl. In one embodiment, R₁₂ is C₂-C₆alkynyl.

In one embodiment, R₁₂ is C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl. In one embodiment, R₁₂ is C₃-C₈ cycloalkyl. In oneembodiment, R₁₂ is heterocyclyl. In one embodiment, R₁₂ is aryl. In oneembodiment, R₁₂ is heteroaryl.

In one embodiment, the compounds of the present disclosure arerepresented by compounds of Formula II:

or pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers, isomers, or tautomers thereof,

wherein:

represents optional double bonds which can form an aromatic whenpresent;

Z₁, Z₂, Z₃, and Z₄ are independently C, N, S, O, N(R₁₀), or C(R₁₀); and

X₁, X₂, X₃, A₁, A₂, Y, R₂, R₃, R₄, R₁₀ are described as herein.

In one embodiment, the compounds of the present disclosure arerepresented by compounds of Formula III:

or pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers, isomers, or tautomers thereof,

wherein:

straight or curved represents optional double bonds that form apartially unsaturated ring or an aromatic ring when present;

Z₁, Z₂, Z₃, and Z₄ are independently C, N, O, N(R₁₀), or C(R₁₀),provided Z₁, Z₂, Z₃, and Z₄ are not all N or N(R₁₀) when

is present and aromatic; provided that no three N or N(R₁₀) areadjacent; provided that Z₁, Z₂, Z₃, and Z₄ are not O when

is present and aromatic; and

X₁, X₂, X₃, A₁, A₂, Y, R₂, R₃, R₄, R₁₀ are described as herein.

In one embodiment, the compound is of formula Ia:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, the compound is of formula Ib:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the D ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, the compound is of formula Ic:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the D ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl; and the T ring represents a C₃-C₁₀ cycloalkyl, C₅-C₈cycloalkenyl, C₃-C₈ spirocycloalkyl, spiroheterocyclyl, heterocyclyl,aryl, or heteroaryl.

In one embodiment, the compound is of formula Id:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the T ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, the compound is of formula Ie:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the T ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, the compound is of formula If;

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the D ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl; and the T ring represents a C₃-C₁₀ cycloalkyl, C₅-C₈cycloalkenyl, C₃-C₈ spirocycloalkyl, spiroheterocyclyl, heterocyclyl,aryl, or heteroaryl.

In one embodiment, the compound is of formula Ig:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, the compound is of formula Ih:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, the compound is of formula Ih-a:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, the compound is of formula Ii:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the T ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, the compound is of formula Ii-a:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the T ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, the compound is of formula Ii or a pharmaceuticallyacceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, ortautomer thereof, wherein the T ring represents a heterocyclyl.

In one embodiment, the compound is of formula Ii-a or a pharmaceuticallyacceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, ortautomer thereof, wherein the T ring represents a heterocyclyl.

In one embodiment, the compound is of formula Ij:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof, wherein the T ring represents aC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, the compound is of formula Ij or a pharmaceuticallyacceptable salt, prodrug, solvate, hydrate, enantiomer, isomer, ortautomer thereof, wherein the T ring represents a heterocyclyl.

In one embodiment, the compound is of formula Ik:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, the compound is of formula Ik-a:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,enantiomer, isomer, or tautomer thereof.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S(O)—, A₂is —C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S(O)—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S(O)—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S(O)—, and Y is —C(R₈)(R₉)—.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S(O)—, A₂is —C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S(O)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S(O)—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S(O)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —S(O)—, A₂is —C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —S(O)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —S(O)—, A₂ is—C(R₈)(R₉)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—S(O)—, and Y is —C(R₈)(R₉)—, wherein R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of A₁, A₂, and Y is —C(R₈)(R₉)—, whereinR₈ and R₉ are halogen.

In one embodiment, at least one of A₁, A₂, and Y is —C(R₈)(R₉)—, whereinR₈ and R₉ are F.

In one embodiment, at least two of A₁, A₂, and Y is —C(R₈)(R₉)—, whereinR₈ and R₉ are halogen.

In one embodiment, at least two of A₁, A₂, and Y is —C(R₈)(R₉)—, whereinR₈ and R₉ are F.

In one embodiment, A₁, A₂, and Y are —C(R₈)(R₉)—, wherein R₈ and R₉ arehalogen.

In one embodiment, A₁, A₂, and Y are —C(R₈)(R₉)—, wherein R₈ and R₉ areF.

In one embodiment, A₁ is —C(R₈)(R₉)—, wherein R₈ and R₉ are halogen.

In one embodiment, A₁ is —C(R₈)(R₉)—, wherein R₈ and R₉ are F.

In one embodiment, A₂ is —C(R₈)(R₉)—, wherein R₈ and R₉ are halogen.

In one embodiment, A₂ is —C(R₈)(R₉)—, wherein R₈ and R₉ are F.

In one embodiment, Y is —C(R₈)(R₉)—, wherein R₈ and R₉ are halogen.

In one embodiment, Y is —C(R₈)(R₉)—, wherein R₈ and R₉ are F.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is H, —NR₈R₉, —P(O)(OR₈)(OR₉),—C(O)R₈, —C(O)NR₈R₉, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, and R₁ is H, —NR₈R₉,—P(O)(OR₈)(OR₉), —C(O)R₈, —C(O)NR₈R₉, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,C₃-C₈ spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is H, —NR₈R₉, —P(O)(OR₈)(OR₉),—C(O)R₈, —C(O)NR₈R₉, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,spirocycloalkyl, spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, and R₁ is H, —NR₈R₉, —P(O)(OR₈)(OR₉), —C(O)R₈,—C(O)NR₈R₉, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, C₃-C₈ spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, spirocycloalkyl,spiroheterocyclyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)— and R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl, aryl,or heteroaryl, wherein the heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl optionallysubstituted with one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyloptionally substituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl optionallysubstituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, and R₁ is heterocyclyl optionally substitutedwith one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is heteroaryl optionallysubstituted with one or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, and R₁ is heteroaryloptionally substituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, and R₁ is heteroaryl optionallysubstituted with one or more R₆.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, and R₁ is heteroaryl optionally substituted withone or more R₆.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, and R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, and R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, and R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, and R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, and R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ and R₃ are independently at each occurrenceH, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, and R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, and R₂ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, and R₂ is halogen.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, and R₂ is halogen.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is H, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is halogen, and R₃ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, RI is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, X is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ is H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ is H, halogen, —OH, —NH₂,—CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, whereinthe alkyl, alkoxy, alkenyl, or alkynyl is optionally substituted withone or more R₇.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, X is C(R₅), A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, X is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form C₃-C₁₀ cycloalkyl,C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formC₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, orheteroaryl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form C₃-C₁₀cycloalkyl, C₅-C₈ cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ and R₃ are independently at each occurrence H,halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, orC₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl isoptionally substituted with one or more R₇, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, Ct-Ce alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, Ct-Ce alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, Ct-Ce alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, Ct-Ce alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ and R₃ are independently at each occurrence H, halogen, —OH,—NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl,wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionally substitutedwith one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, wherein theheterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, halogen,—CN, —OR₈, —NR₈R₉, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₅-C₈ cycloalkenyl,heterocyclyl, aryl, or heteroaryl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is—C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with one or moreR₆, R₂ is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ and R₃ are independently at eachoccurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy, alkenyl, oralkynyl is optionally substituted with one or more R₇, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is H, R₃ is H, and R₄ and R₉ canform heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is H, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, R₂ is halogen, R₃ is H, and R₄ and R₉can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is H, R₃ is H, and R₄ isH.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is H, R₃ is H, and R₄ isH.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is halogen, R₃ is H, andR₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is halogen, R₃ is H, andR₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is H, R₃ is H, and R₄ andR₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is H, R₃ is H, and R₄ andR₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl, aryl, or heteroaryl, wherein the heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ isheterocyclyl optionally substituted with one or more R₆, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —O—, A₂ is —C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is halogen, R₃ is H, andR₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), wherein R₅ is C₁-C₆alkyl, A₁ is —C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryloptionally substituted with one or more R₆, R₂ is halogen, R₃ is H, andR₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is H, R₃ is H,and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, RI is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is H, R₃ is H,and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, RI is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ and R₃ are independently at each occurrence H, halogen,—OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆alkynyl, wherein the alkyl, alkoxy, alkenyl, or alkynyl is optionallysubstituted with one or more R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ and R₃are independently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is H, R₃ is H,and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ is H,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is H, R₃ is H,and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, RI is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence oxo, halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉,—NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl can be optionally substituted with oneor more R₁₀, R₂ is halogen, R₃ is H, and R₄ and R₉ can formheterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrence oxo,halogen, —CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈,—S(O)₂R₈, —NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, whereineach alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl can be optionally substituted with one or more R₁₀, R₂ ishalogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence oxo, halogen,—CN, —OR₈, —C(O)R₈, —C(O)OR₈, —C(O)NR₈R₉, —NR₈C(O)R₉, —S(O)R₈, —S(O)₂R₈,—NR₈S(O)₂R₉, —S(O)₂NR₈R₉, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl,alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroarylcan be optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is H, R₃ is H, and R₄ isH.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ is H, andR₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is H, R₃ is H, and R₄ isH.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is halogen, R₃ is H, andR₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, RI is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ is H.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is halogen, R₃ is H, andR₄ is H.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, RI is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂and R₃ are independently at each occurrence H, halogen, —OH, —NH₂, —CN,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein thealkyl, alkoxy, alkenyl, or alkynyl is optionally substituted with one ormore R₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ and R₃ areindependently at each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl,alkoxy, alkenyl, or alkynyl is optionally substituted with one or moreR₇, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ and R₃ are independentlyat each occurrence H, halogen, —OH, —NH₂, —CN, C₁-C₆ alkyl, C₁-C₆alkoxy, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein the alkyl, alkoxy,alkenyl, or alkynyl is optionally substituted with one or more R₇, andR₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is H, R₃ is H, and R₄and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ is H, andR₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, RI is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is H, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is H, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is H, R₃ is H, and R₄and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, orheteroaryl, wherein the heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl,wherein the heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl, aryl, or heteroaryl, whereinthe heterocyclyl, aryl, or heteroaryl is optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is halogen, R₃ is H, andR₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heterocyclyl optionally substituted withone or more R₆, wherein R₆ is independently at each occurrence C₁-C₆alkyl optionally substituted with one or more R₁₀, R₂ is halogen, R₃ isH, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, at least one of X₁, X₂, or X₃ is N, A₁ is—C(R₈)(R₉)—, A₂ is —O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionallysubstituted with one or more R₆, wherein R₆ is independently at eachoccurrence C₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂is halogen, R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —O—, A₂ is—C(R₈)(R₉)—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substitutedwith one or more R₆, wherein R₆ is independently at each occurrenceC₁-C₆ alkyl optionally substituted with one or more R₁₀, R₂ is halogen,R₃ is H, and R₄ and R₉ can form heterocyclyl.

In one embodiment, one of X₁, X₂, X₃ is C(R₅), A₁ is —C(R₈)(R₉)—, A₂ is—O—, Y is —C(R₈)(R₉)—, R₁ is heteroaryl optionally substituted with oneor more R₆, wherein R₆ is independently at each occurrence C₁-C₆ alkyloptionally substituted with one or more R₁₀, R₂ is halogen, R₃ is H, andR₄ and R₉ can form heterocyclyl.

In one embodiment, suitable compounds of the disclosure are andpharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers, isomers, and tautomers thereof are described in Table 1.

TABLE 1 Compound No. Compound Name 1(15R)-10-(2-methyl-3-pyridyl)-13,17-dioxa-3,5,7,8-tetrazapentacyclo[13.6.1.04,12.05,9.018,22] docosa-1(22),4(12),6,8,10,18,20-heptaene 3(S)-1-(4-(7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one 41-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one 512-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine 612-fluoro-4-(2-methylpyridin-3-yl)-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine 7(S)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 8(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 9(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one 10(S)-12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine11 (S)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 12(S)-12-fluoro-4-(oxetan-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine13(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine14 4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine 15(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine16 methyl (S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylate 17(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine18(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine19 (S)-12-fluoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine20 (S)-12-fluoro-4-(2-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine21 (S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine22(S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine23(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 24 (S)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one 25 (R)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one 26 (S)-4-ethyl-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine27 (S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine28(S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine29 (S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine30 (S)-12-fluoro-4-(2-methoxypyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine31 (S)-12-fluoro-4-(6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine32(S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine33(S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine34 (S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine35(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)propan-2-ol 36(S)-12-fluoro-4-(4-(methylsulfonyl)phenyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine37 (S)-12-fluoro-N,N-dimethyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxamide 38(S)-12-fluoro-N-methyl-N-(2,2,2-trifluoroethyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxamide 39(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine40(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine41 (S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine42 (S)-12-fluoro-4-(5-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine43(S)-12-fluoro-4-(3-fluoro-5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine44 (S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine45(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine46 (S)-12-fluoro-4-(5-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine47 (S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine48(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)benzonitrile 49(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-3-methylbenzonitrile 50(S)-12-fluoro-4-(2-methoxypyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine51(S)-3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridine 1-oxide 52(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine53 (S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine54 (S)-12-fluoro-4-(4-methylpyridazin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine55 (S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine56 (S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine57(S)-12-fluoro-4-(2-methoxy-4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine58(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N,4-trimethylpyrimidine-2-carboxamide 59(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpicolinamide 60(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine61(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine62 (S)-4-(3,5-dimethylisoxazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine63(S)-12-fluoro-4-(1-(2-methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 64(S)-12-fluoro-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxamide 65(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine66 (S)-12-fluoro-4-(6-methylpyridazin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine67(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine68(S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 69(S)-4-(2-(difluoromethyl)-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 70(S)-4-(4-(difluoromethyl)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine71(S)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine72 (S)-4-(1-ethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine73(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine74(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol75(S)-12-fluoro-4-(1-isopropyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine76(S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine77 (S)-12-fluoro-4-(2-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine78(S)-4-(2-(difluoromethoxy)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine79 (S)-12-fluoro-4-(3-methyl-1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine80 (S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine81(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylpropan-2-ol82(S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-ol83(S)-12-fluoro-4-(2-(trifluoromethoxy)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine84 (S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 85(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 86(S)-4-(4,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine87(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine88 (S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 89(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine90 (S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 91(S)-12-fluoro-4-(pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine92 (S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine93 (S)-12-fluoro-4-(thiazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine94 (S)-12-fluoro-4-(6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine95 (S)-12-fluoro-4-(3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine96 (S)-4-(2-ethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine97(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one 98(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine99(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine100(S)-4-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine101 (S)-4-(5-chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine102(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine103(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpyridin-2-amine 104(S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine105(S)-12-fluoro-4-(2-methoxy-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine106(S)-12-fluoro-4-(6-methoxy-2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine107(S)-12-fluoro-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine108(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpyrimidin-2-amine 109(S)-4-(2-ethoxypyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine110(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine111(S)-12-fluoro-4-(5-fluoro-2-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine112(S)-12-fluoro-4-(6-(trifluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine113(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine114(S)-12-fluoro-4-(2-(trifluoromethyl)pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine115(S)-12-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 116(S)-12-fluoro-4-(6-morpholinopyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine117(S)-12-fluoro-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine118(S)-12-fluoro-4-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 119(S)-12-fluoro-4-(2-(trifluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine120(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine121 (S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[r,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine122(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine123 (S)-12-fluoro-4-(6-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine124(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-amine 125(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,1-dimethyl-1H-pyrazol-3-amine126(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N,1-trimethyl-1H-pyrazol-3-amine127(S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)methanamine128(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N-methylmethanamine 129(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylmethanamine 130(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 131(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-ol132(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylethan-1-amine 133(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine134(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine135(S)-4-(1,4-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine136(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine137(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine138(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine139(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine140(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine141(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 142(S)-12-fluoro-4-(1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine143(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol144(S)-4-(3-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 145(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine146(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine147(S)-12-fluoro-4-(1,2,4-trimethyl-1H-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine148(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine149 (S)-12-fluoro-4-(4-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine150 (S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine151 (S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine152(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine153(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine154(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine155 (S)-12-fluoro-4-(2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine156 (S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine157(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine158(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine159 (S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine160 (S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine161 (S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine162 (S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine163 (S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine164 (S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine165 (S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine166(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine167(S)-4-(3-(difluoromethoxy)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 168(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine169(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile 170(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile171(S)-4-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine 172(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[r,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile174 (S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[r,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid 175(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[r,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide176(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[r,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide 177(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[r,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylic acid 178(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine179(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-3-amine 181methyl4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidine-1-carboxylate 1824-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine 18312-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine 184(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine185 (R)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine186(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile 187(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-ol 188(S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine189 (S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine190(S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine191(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)-N-methylpropanamide 192(S)-3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-4-ol 193(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one194(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-3-ol 195(S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)methanol 196(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-4-ol 197(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-ol 1981-(4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidin-1-yl)ethan-1-one

In another embodiment of the invention, the compounds of Formula I areenantiomers. In some embodiments the compounds are (S)-enantiomer. Inother embodiments the compounds may also be (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

In another embodiment of the invention, the compounds of Formula Icontain isotopes of atoms forming the structure of Formula I. Isotopesherein means, each of two or more forms of the same element (e.g., H andD; ¹²C and ¹³C) that contain equal numbers of protons but differentnumbers of neutrons in their nuclei, and hence differ in relative atomicmass.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis or irons configuration. All tautomeric formsare also intended to be included.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of a disease ordisorder associated with modulation of embryonic ectoderm development(EED) and/or Polycomb Repressive Complex 2 (PRC2). The method involvesadministering to a patient in need thereof an effective amount of thecomposition or compound of Formula I.

Another aspect of the invention relates to a method of a disease ordisorder associated with modulation of embryonic ectoderm development(EED). The method involves administering to a patient in need thereof aneffective amount of the composition or compound of Formula I.

Another aspect of the invention is directed to a method treating adisease or disorder associated with modulation of Polycomb RepressiveComplex 2 (PRC2). The method involves administering to a patient in needthereof an effective amount of the composition or compound of Formula I.

Another aspect of the invention is directed to a method treating adisease or disorder associated with modulation of Polycomb RepressiveComplex 2 (PRC2). The method involves administering to a patient in needthereof an effective amount of the composition or compound of Formula I.

In one embodiment, the disease or disorder is a blood disorder.

In one embodiment, the blood disorder is Acute lymphoblastic leukemia(ALL), Acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia,APL), Amyloidosis, Anemia, Aplastic anemia, Bone marrow failuresyndromes, Chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia(CML), Deep vein thrombosis (DVT), Diamond-Blackfan anemia, Dyskeratosiscongenita (DKC), Eosinophilic disorder, Essential thrombocythemia,Fanconi anemia, Gaucher disease, Hemochromatosis, Hemolytic anemia,Hemophilia, Hereditary spherocytosis, Hodgkin's lymphoma, Idiopathicthrombocytopenic purpura (ITP), Inherited bone marrow failure syndromes,Iron-deficiency anemia, Langerhans cell histiocytosis, Large granularlymphocytic (LGL) leukemia, Leukemia, Leukopenia, Mastocytosis,Monoclonal gammopathy, Multiple myeloma, Myelodysplastic syndromes(MDS), Myelofibrosis, Myeloproliferative neoplasms (MPN), Non-Hodgkin'slymphoma, Paroxysmal nocturnal hemoglobinuria (PNH), Pernicious anemia(B12 deficiency), Polycythemia vera, Porphyria, Post-transplantlymphoproliferative disorder (PTLD), Pulmonary embolism (PE),Shwachman-Diamond syndrome (SDS), sickle cell disease (SCD),Thalassemia, Thrombocytopenia, Thrombotic thrombocytopenic purpura(TTP), Venous thromboembolism, Von Willebrand disease, or Waldenstrom'smacroglobulinemia (lymphoplasmacytic lymphoma).

In one embodiment, the blood disorder is sickle cell disease.

In one embodiment, the blood disorder is thalassemia (e.g.,β-thalassemia).

In one embodiment, the disease or disorder is cancer. In one embodiment,the disease or disorder is selected from diffused large B cell lymphoma,follicular lymphoma, other lymphomas, leukemia, multiple myeloma,mesothelioma, gastric cancer, malignant rhabdoid tumor, hepatocellularcarcinoma, prostate cancer, breast carcinoma, bile duct and gallbladdercancers, bladder carcinoma, brain tumors including neuroblastoma,schwannoma, glioma, glioblastoma and astrocytoma, cervical cancer, coloncancer, melanoma, endometrial cancer, esophageal cancer, head and neckcancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer,pancreatic cancer, renal cell carcinoma, rectal cancer, thyroid cancers,parathyroid tumors, uterine tumors, and soft tissue sarcomas.

The present invention further provides a method of treating sickle celldisease (SCD) or β-thalassemia. The method comprises administering to apatient in need thereof an effective amount of the compound of FormulaI. In one embodiment, the administration results in modulation of EEDregulated expression of a fetal orthologue (e.g., fetal hemoglobin(e.g., HbF or α2γ2)) in the blood of the patient. In one embodiment, themodulation results in compensation for the function of one or moremutations affecting the β-globin genes in adult hemoglobin A (α2β2).

In one embodiment, the disease or disorder is a disease or disordercapable of being treated by reactivation of a developmentally regulatedfetal ortholog in another disease or another tissue.

The present invention further provides a method of treating sickle celldisease (SCD) or β-thalassemia. The method comprises administering to apatient in need thereof an effective amount of the composition orcompound of Formula I. In one embodiment, the administration results inmodulation of EED regulated expression of a fetal orthologue (e.g.,fetal hemoglobin (e.g., HbF or α2γ2)) in the blood of the patient. Inone embodiment, the modulation results in compensation for the functionof one or more mutations affecting the β-globin genes in adulthemoglobin A (α2β2).

The present invention further provides methods of treating thoracicaortic aneurysm, coronary heart disease, stenotic disease, pulmonaryartery hypertension (PAH), liver fibrosis, allergic inflammation,retinitis pigmentosa, septic shock, herpes simplex virus, humancytomegalovirus, α-thalassemia, familial atrial fibrillation, commonvariable immunodeficiency, aneurysm-osteoarthritis syndrome, andacquired immunodeficiency syndrome. The method comprises administeringto a patient in need thereof an effective amount of the compound ofFormula I.

In one embodiment, the method of the present disclosure furthercomprises administering to a patient in need thereof an effective amountof at least one additional therapeutic agent. In one embodiment, atleast one therapeutic agent is selected from anti-cancer agents,immunomodulators, anti-allergic agents, anti-emetics, pain relievers,cytoprotective agents, or combinations thereof. In one embodiment, atleast one therapeutic agent is hydroxyurea, L-glutamine, gene therapies(e.g., CRISPR and AAV or other viral HBG delivery), PDE9 inhibitors, RBCanti-adhension therapies (e.g., P-selectin), or other compoundstargeting transcriptional regulation. In one embodiment, at least onetherapeutic agent is an EZH2 inhibitor. In one embodiment, at least onetherapeutic agent isN-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide(tazemetostat),(2R)-7-chloro-2-[4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide(valemetostat, DS-3201b),N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-methyl-1-[(1R)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl]indole-3-carboxamide(CPI-1205),(S)-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide(GSK2816126), or(R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one(PF-06821497), or SHR2554, or a combination thereof. In one embodiment,at least one therapeutic agent is hydroxyurea. In one embodiment, atleast one therapeutic agent is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(voxelotor, GBT-440), P-Selectin antibodies, or L-Glutamine, or acombination thereof. In one embodiment, the at least one therapeuticagent is selected from anti-adhesion agents. In one embodiment, the atleast one therapeutic agent is crizanlizumab (SEG101),(2S)-2-[(2R,3R,4S,5S,6R)-3-benzoyloxy-2-[(1R,2R,3S,5R)-3-[(2,4-dioxo-1H-pyrimidine-6-carbonyl)amino]-5-[2-[[2-[2-[2-oxo-2-[(3,6,8-trisulfonaphthalen-1-yl)amino]ethoxy]ethoxy]acetyl]amino]ethylcarbamoyl]-2-[(2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxycyclohexyl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3-cyclohexylpropanoicacid (rivipansel, GMI-1070), sevuparin,6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(oxan-4-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one(PF-04447943), inclacumab (LC1004-002), or3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine(miransertib, ARQ 092), or combinations thereof. In one embodiment, theat least one therapeutic agent is selected from other anti-sicklingagents. In one embodiment, at least one therapeutic agent is2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde(voxelotor, GBT-440) or6-[(3S,4S)-4-Methyl-1-(2-pyrimidinylmethyl)-3-pyrrolidinyl]-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(IMR-687), or combinations thereof. In one embodiment, at least onetherapeutic agent is selected from detoxification agents. In oneembodiment, at least one therapeutic agent is LJPC-401. In oneembodiment, at least one therapeutic agent is selected fromanti-inflammatory agents, anti-thrombiotic agents, or combinationsthereof. In one embodiment, the at least one therapeutic agent is(1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol(Brilinta, tricagrelor),(2R)-3,3,3-trifluoro-2-[[[5-fluoro-2-[l-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]amino]methyl]-2-hydroxypropanamide(olinciguat), or NKTT120, or combinations thereof. In one embodiment, atleast one therapeutic agent is sanguinate. In one embodiment, at leastone therapeutic agent causes disruption of PRC2. In one embodiment, atleast one therapeutic agent is AZD9291.

Another aspect of the invention is directed to a method of inducingfetal hemoglobin (hemoglobin γ (HBγ), or HbF) expression in erythroidcells. The method involves administering to a patient in need thereof aneffective amount of the composition or compound of Formula I.

In one embodiment, the composition or compound of Formula I inducesupregulation of mRNA levels (e.g., HBG1 or HBG2, with sequences shownherein) or upregulation of fetal hemoglobin protein (HBγ) that resultsin an elevation in HbF protein.

In one embodiment, the method further involvs administering to a patientin need thereof one or more additional therapeutic agents thatupregulate HbF and/or reduce or alleviate one or more symptoms of SCDand/or β-thalassemia (e.g., vaso-occlusion and anemia).

Hemoglobin Subunit Gamma-1 (HBG1) Sequence (SEQ ID NO: 1):MGHFTEEDKATITSLWGKVNVEDAGGETLGRLLVVYPWTQRFFDSFGNLSSASAIMGNPKVKAHGKKVLTSLGDAIKHLDDLKGTFAQLSELHCDKLHVDPENFKLLGNVLVTVLAIHFGKEFTPEVQASWQKMVTAVASALSSRYHHemoglobin Subunit Gamma-2 (HBG2) sequence (SEQ ID NO: 2):MGHFTEEDKATITSLWGKVNVEDAGGETLGRLLVVYPWTQRFFDSFGNLSSASAIMGNPKVKAHGKKVLTSLGDAIKHLDDLKGTFAQLSELHCDKLHVDPENFKLLGNVLVTVLAIHFGKEFTPEVQASWQKMVTGVASALSSRYHHemoglobin Subunit Alpha-1 (HBA1) amino acid sequence (SEQ ID NO: 3):MVLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGHGKKVADALTNAVAHVDDMPNALSALSDLHAHKLRVDPVNFKLLSHCLLVTLAAHLPAEFTPAVHASLDKFLASVSTVLTSKYRHemoglobin Subunit Alpha-2 (HBA2) amino acid sequence (SEQ ID NO: 4)MVLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGHGKKVADALTNAVAHVDDMPNALSALSDLHAHKLRVDPVNFKLLSHCLLVTLAAHLPAEFTPAVHASLDKFLASVSTVLTSKYR

Another aspect of the invention is directed to use of a compound ofFormula I for treating a disease or disorder associated with themodulation of embryonic ectoderm development (EED) and/or PolycombRepressive Complex 2 (PRC2).

Another aspect of the invention is directed to use of a compound ofFormula I for treating a disease or disorder associated with themodulation of embryonic ectoderm development (EED).

Another aspect of the invention is directed to use of a compound ofFormula I for treating a disease or disorder associated with themodulation of Polycomb Repressive Complex 2 (PRC2).

Another aspect of the invention is directed to a compound of Formula Ifor use in the manufacture of a medicament for treating a disorder ordisease associated with embryonic ectoderm development (EED) and/orPolycomb Repressive Complex 2 (PRC2).

Another aspect of the invention is directed to a compound of Formula Ifor use in the manufacture of a medicament for treating a disorder ordisease associated with embryonic ectoderm development (EED).

Another aspect of the invention is directed to a compound of Formula Ifor use in the manufacture of a medicament for treating a disorder ordisease associated with Polycomb Repressive Complex 2 (PRC2).

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, the pharmaceutical composition further comprises atleast one additional therapeutic agent. In one embodiment, the at leastone therapeutic agent is selected from other anti-cancer agents,immunomodulators, anti-allergic agents, anti-emetics, pain relievers,cytoprotective agents, and combinations thereof. In one embodiment, theat least one therapeutic agent is selected from hydroxyurea,L-glutamine, gene therapies (e.g., CRISPR and AAV or other viral HBGdelivery), PDE9 inhibitors, RBC anti-adhension therapies (e.g.,P-selectin), and other compounds targeting transcriptional regulation.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, poly orthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.1 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.1, 0.5, 5, 20, 50, 75, 100,150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present invention includes bothpossible stereoisomers (unless specified in the synthesis) and includesnot only racemic compounds but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereo specific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. General methods include but arenot limited to those methods described below. Moreover, the suitablestarting material readily available and known by one of skilled in theart can be selected to arrive at specific compounds of the presentdisclosure. Compounds of the present invention Formula I can besynthesized by following the steps outlined in Schemes 1-4, wherein R₁,R₂, and R₃ are defined in Formula I. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

The general way of preparing a common intermediate 1g is outlined inScheme 1, wherein R₂ and R₃ are defined in Formula 1. Deprotonation of1a followed by a reaction with a formylation agent, such as DMF, yieldsintermediate 1b which can be treated with boron tribromide to deprotectthe phenolic moiety to afford 1c. Protection of the aldehyde results inintermediate 1d which can be reacted with commercially available epoxide1e to afford 1f. Treatment with a strong base, such as n-butyl lithium,yields the common intermediate 1g that can be converted in a number ofways to the final compounds.

The general way of preparing target compound 2l is outlined in Scheme 2,wherein R₁, R₂ and R₃ are defined in Formula 1.5-Bromo-6-chloro-2-nitropyridin-3-ol (Example 2) is reacted with thealcohol 1g under Mitsunobu conditions. Nitro group reduction followed bythe aldehyde deprotection step afforts intermediate 2d which can beconverted into an alcohol and subsequently into a leaving group such aschloride 2f. The cyclization step can be conducted, for example, withcesium carbonate and tetrabutyl ammonium iodide. Boc protection affordsintermediate 2h which then can be reacted with hydrazine hydrate toafford intermediate 2i. The triazole ring formation can be accomplished,for example, by means of triethyl orthoformate, thus affording a commonintermediate 2j. The Boc group can be removed in acidic conditionsfollowed by coupling steps with a variety of reagents to result in finalproducts 2l. Alternatively, the coupling step can be performed on theBoc-protected intermediate 2j with a subsequent Boc-deprotection step.

Another general way of preparing cyclization precursor 2e is outlined inScheme 3, wherein R₂ and R₃ are defined in Formula 1. Iodide 3b isobtained from 5-bromo-6-chloropyridin-2-amine by means ofA-iodosuccinimidc and the amino group is protected by alkylation with,for example, p-methoxybenzyl chloride. The resulting intermediate 3c canbe coupled with the alcohol of 1g under copper-mediated conditions, forexample. The dioxolane moiety is cleaved under acidic conditions, forexample with aqueous HCl, and the resulting aldehyde is converted intoalcohol 3f with a reducing agent, such as sodium borohydride. Fulldeprotection of the aminogroup with a strong acid, such as TFA, resultsin intermediate 2e, which can then be converted into the final productsas described in Scheme 2.

Another general way of preparing the common intermediate 2k is outlinedin Scheme 4, wherein R₂ and R₃ are defined in Formula 1. Nosylprotection of the amino group in intermediate 2c with a subsequentaldehyde deprotection affords compound 4b, which can be reduced toprovide alcohol 4c. The cyclization can be accomplished under Mitsunobuconditions to result in intermediate 4d. Removal of the nosyl protectinggroup with PhSH affords common intermediate 2k which can then beconverted into the final products as described in Scheme 2.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Abbreviations used in the following examples and elsewhere herein are:

-   23° C. room temperature;-   Ac₂O acetic anhydride-   ACN acetonitrile-   AcOH or HO Ac acetic acid-   aq aqueous-   Boc₂O di-tert-butyl dicarbonate-   BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate-   (Bpin)₂ bis(pinacolato)diboron;-   CDCl₃ deuterated chloroform-   CD₃OD deuterated methanol-   Comins' reagent N-bis(trifluoromethanesulfonimide);-   δ chemical shift-   DBDMH 1,3-dibromo-5,5-dimethylhydantoin-   DCM dichloromethane or methylene chloride-   DCE 1,2-dichloroethane-   DEAD diethyl azodicarboxylate-   DIAD diisopropyl azodicarboxylate-   DIBAL-H diisobutylaluminum hydride-   DIEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DME dimethoxyethane-   DMF AA-dimethylformamide-   DMP Dess-Martin Periodinane-   DMSO dimethylsulfoxide-   DMSO-d₆ deuterated dimethylsulfoxide-   DPPA diphenyl phosphoryl azide-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   EDCI A-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   ee enantiomeric excess-   eq. or equiv. equivalent-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   FA formate-   Fe iron-   h or hr hour(s)-   ¹H NMR proton nuclear magnetic resonance-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HFIP hexafluoroisopropanol-   HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate-   HPLC high performance liquid chromatography-   Hz hertz-   IPA isopropyl alcohol-   KOAc potassium acetate-   LAH lithium aluminum hydride-   LCMS liquid chromatography/mass spectrometry-   LC-MS liquid chromatography/mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   m minute(s)-   (M+a) mass+1-   m-CPBA m-chloroperbenzoic acid-   MBTE methyl tert-butyl ether-   MeOH methanol-   MeMgBr methyl magnesium bromide-   MPLC medium-pressure liquid chromatography-   MS mass spectrometry-   NaHMDS sodium bis(trimethylsilyl)amide-   NCS N-chlorosuccinimide-   NMP N-methylpyrrolidone-   NMR nuclear magnetic resonance-   Ns nosyl (4-nitrobenzenesulfonyl)-   Pd(dppf)Cl₂    [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Palladium tetrakis Tetrakis(triphenylphosphine)palladium(0)-   PMB para-methoxybenzyl-   t_(R) retention time-   sat. saturated-   SFC supercritical fluid chromatography-   TBAI tetrabutylammonium iodide-   TBDMS-Cl tert-butyl dimethylsilyl chloride-   TBME tert-butyl methyl ether-   TEA trimethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   HFIP hexafluoroisopropanol-   THF tetrahydrofuran-   TLC thin layer chromatography-   OTf trifluoromethanesulfonate-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

General Methods

All temperatures are in degrees Celsius (° C.) and are uncorrected.Reagent grade chemicals and anhydrous solvent were purchased fromcommercial sources and unless otherwise mentioned, were used withoutfurther purification. Silica gel chromatography was performed onTeledyne Isco instruments using pre-packaged disposable SiO₂ stationaryphase columns with eluent flow rate range of 15 to 200 mL/min, UVdetection (254 and 280 nm). Reverse phase preparative HPLC was carriedout using C18 columns, UV detection (214 and 254 nm) eluting withgradients of MeCN in water (0.03% (NH₄)₂CO₃/0.375% NH₄OH) or MeCN inwater (0.1% HCOOH). The analytical HPLC chromatograms were performedusing an Agilent 1100 series instrument with DAD detector (190 nm to 300nm). The mass spectra were recorded with a Waters Micromass ZQ detectorat 130° C. The mass spectrometer was equipped with an electrospray ionsource (ESI) operated in a positive ion mode and was set to scan betweenm/z 150-750 with a scan time of 0.3 s. Unless otherwise specified,products and intermediates were analyzed by HPLC/MS on a Gemini-NX (5μM, 2.0×30 mm) using a high pH buffer gradient of 5% to 100% of MeCN inwater (0.03% (NH₄)₂CO₃/0.375% NH₄OH) over 2.5 min at 1.8 mL/min for a3.5 min run (B05) and EVO C18 (5 μM, 3.0×50 mm) using a low pH buffergradient of 5% to 100% of MeCN in water (0.1% HCOOH) over 2.5 min at 2.2mL/min for a 3.5 min run (A05). Unless otherwise specified, prep-HPLCpurification was performed using the following eluents: MeCN/10 mMaqueous NH₄HCO₃ for the “neutral conditions” method, MeCN/0.04% aqueousHCl for the “HCl conditions” method, and MeCN/0.2% aqueous HCOOH for the“FA conditions” method. The ¹H NMR chemical shifts are referenced tosolvent peaks, which in ¹H NMR appear at 7.26 ppm for CDCl₃, 2.50 forDMSO-d6, and 3.31 ppm for CD₃OD.

Example 1: 5-bromo-6-chloropyridin-3-ol

A mixture of NaNO₂ (31.9 g, 4620 mmol, 1.20 eg) in water (80.0 mL) wasadded to an ice-cooled solution of 5-bromo-6-chloropyridin-3-amine (80.0g, 386 mmol, 1.00 eq) in H₂SO₄ (567 g, 2.89 mol, 308 mL, 50% purity,7.50 eq) at 0° C., and then the mixture was stirred at 25° C. for 30mins. The mixture was added to AcOH (400 mL) at 100° C. The mixture wasstirred at 100° C. for 12 h. LCMS showed the reaction was complete. Themixture was concentrated under reduced pressure. The mixture was addedto ice-water (2000 mL) and adjusted the pH to 6-7 using sat. aq. Na₂CO₃.The mixture was extracted with EtOAc (5000 mL). The organic layer waswashed with brine (2000 mL), dried over Na₂CO₃, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 4/1,Petroleum ether/Ethyl acetate=2/1, R_(f)=0.56).5-bromo-6-chloropyridin-3-ol (52.0 g, crude) was obtained as a yellowsolid. ¹H NMR CDCl₃ 400 MHz, δ=ppm 7.95 (d, J=2.6 Hz, 1H), 7.45 (d,J=2.6 Hz, 1H).

Example 2: 5-bromo-6-chloro-2-nitropyridin-3-ol

The reaction was set up in two separate batches. A mixture of5-bromo-6-chloropyridin-3-ol (46.0 g, 220 mmol, 1.00 eq) in H₂SO₄ (138mL, 98% purity) was stirred at 0° C. for 75 min. H₂SO₄ (42.3 g, 423mmol, 23.0 mL, 98% purity, 1.92 eq) and fuming HNO₃ (19.3 g, 294 mmol,13.8 mL, 96% purity, 1.33 eq) was added to the reaction mixture at 0° C.The mixture was stirred at 0° C. for 2 h. After stirring for 2 h, themixture was stirred at 20° C. for 12 h. LCMS showed that a small amountof 5-bromo-6-chloropyridin-3-ol remained and the desired mass wasdetected. The two reaction mixtures were combined and added to ice-water(3000 mL) and stirred at 20° C. for 1 hr. The mixture was filtered andthe filter cake was dried under reduced pressure to give5-bromo-6-chloro-2-nitropyridin-3-ol (83.0 g, crude) as a yellow solid.¹H NMR DMSO-d₆ 400 MHz, δ=ppm 7.97 (s, 1H).

Example 3: 2-bromo-6-fluoro-3-methoxybenzaldehyde

The reaction was set up in 3 separate batches. To a solution of2-bromo-4-fluoro-1-methoxybenzene (170 g, 829 mmol, 1.00 eq) in THF(2500 mL) was added LDA (2 M, 456 mL, 1.10 eq) at −78° C. undernitrogen. The mixture was stirred at −78° C. for 1 hr, then DMF (121 g,1.66 mol, 128 mL, 2.00 eq) was added under −65° C. The reaction mixturewas stirred at −65° C. for 1 hr. TLC (Petroleum ether:Ethyl acetate=3:1,R_(f)=0.6) detected one major new spot with larger polarity. Each batchwas quenched by addition of water (700 mL) and then the organic solventwas evaporated. The three batches of the remaining aqueous phase werecombined and extracted with EtOAc (1000 mL*3). The combined organiclayers were washed with brine (1000 mL) and dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was triturated withMTBE (1000 mL) and filtered to afford2-bromo-6-fluoro-3-methoxybenzaldehyde (600 g, crude) as a yellow solid.¹H NMR CDCl₃ 400 MHz, δ=ppm 10.39 (s, 1H), 7.19-7.03 (m, 2H), 3.93 (s,3H).

Example 4: 2-bromo-6-fluoro-3-hydroxybenzaldehyde

The reaction was set up in 3 separate batches. To a solution of2-bromo-6-fluoro-3-methoxybenzaldehyde (165 g, 708 mmol, 1.00 eq) in DCM(2000 mL) was added BBr₃ (408 g, 1.63 mol, 157 mL, 2.30 eq) dropwiseover 0.5 hr while keeping inner temperature between 0-10° C. under N₂.The mixture was stirred at 25° C. for 2 h under N₂. TLC (Petroleumether:Ethyl acetate=3:1, R_(f)=0.25) detected one major new spot withhigher polarity. The reaction mixture was quenched with water (2500 mL)and extracted with EtOAc (1000 mL*3). The organic layers from the threebatches were combined, washed with brine (800 mL), dried over Na₂SO₄,filtered and then concentrated under reduced pressure. The residue waswashed with PE/EtOAc (1/1, 600 mL) and filtered, the filter cake wasdried in vacuum to afford 2-bromo-6-fluoro-3-hydroxybenzaldehyde (408 g,1.86 mol, 87% yield) as a yellow solid. ¹H NMR CDCl₃ 400 MHz, δ=ppm10.32 (s, 1H), 7.28-7.22 (m, 1H), 7.15-7.05 (m, 1H), 5.90 (s, 1H).

Example 5: 2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenol

To a solution of 2-bromo-6-fluoro-3-hydroxybenzaldehyde (136 g, 621mmol, 1.00 eq), ethylene glycol (193 g, 3.10 mol, 173 mL, 5.00 eq) intoluenetoluene (2000 mL) was added TsOH (10.7 g, 62.1 mmol, 0.100 eq) at25° C. The mixture was stirred at 130° C. for 8 h under N₂. Threeparallel reactions were set up. LC-MS showed no2-bromo-6-fluoro-3-hydroxybenzaldehyde was remained. Several new peakswere shown on LC-MS and the desired mass was detected. Each batch of thereaction mixture was cooled to room temperature and concentrated to thethird of the initial volume. The residual solution was then diluted withthe saturated NaHCO₃ solution (1000 mL) and extracted with EtOAc (300mL*3). The combined organic layers were washed with brine (200 mL),dried over Na₂SO₄, filtered and concentrated to provide the titlecompound as a solid. The three batches were combined and the residue wastriturated with MTBE (100 mL) and filtered, the filter cake was2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenol.2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenol (355 g, 1.35 mol, 72%yield) was obtained as a white solid. ¹H NMR CDCl₃ 400 MHz, δ=ppm7.08-6.92 (m, 2H), 6.28 (s, 1H), 5.67 (s, 1H), 4.33-4.20 (m, 2H),4.14-4.01 (m, 2H).

Example 6:(R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-1,3-dioxolane

To a mixture of NaH (18.2 g, 456 mmol, 60% purity, 1.2 eq) in DMF (700mL) was added dropwise 2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenol (100g, 380 mmol, 1.00 eq) in DMF (500 mL) at 0° C. The mixture was allowedto warm up to 25° C. and stirred for 0.5 hr. Then (R)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (98.6 g, 380 mmol, 1.00 eq) in DMF (500 mL) wasadded dropwise at 0° C. and the mixture was stirred at 25° C. for 12 h.HPLC showed that some 2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenolremained. Additional (R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (19.7g, 76.0 mmol, 0.2 eq) in DMF (100 mL) was added dropwise at 25° C. andthe mixture was stirred at 25° C. for 4 h. HPLC showed no2-bromo-3-(1,3-dioxolan-2-yl)-4-fluorophenol remained. The mixture wasquenched by the addition of water (2500 mL), filtered, and the filtercake was dried under reduced pressure. Then mother liquor was extractedwith EtOAc (1000 mL*3). The combined organic layers were washed withbrine (1000 mL), dried over Na₂SO₄, filtered, and concentrated to asolid. The solid and the filter cake were combined and triturated withMTBE (100 mL) and filtered to afford(R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-1,3-dioxolane (105g, 329 mmol, 86% yield) as a white solid. ¹H NMR CDCl₃ 400 MHz, δ=ppm7.06-6.99 (m, 1H), 6.99-6.94 (m, 1H), 6.42 (d, J=1.0 Hz, 1H), 4.34-4.21(m, 3H), 4.13-3.98 (m, 3H), 3.40 (tdd, J=5.3, 4.1, 2.8 Hz, 1H),2.99-2.90 (m, 1H), 2.85 (dd, J=4.9, 2.7 Hz, 1H).

Example 7:(S)-(4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methanol

To a mixture of(R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-1,3-dioxolane (113g, 352 mmol, 1.00 eq) in THF (1200 mL) was added dropwise n-BuLi (2.5 M,169 mL, 1.20 eq) at −78° C. The mixture was stirred at −78° C. for 2 hunder N₂. TLC (Petroleum ether:Ethyl acetate=2:1, R_(f)=0.24) detectedone major new spot with higher polarity. LC-MS showed no(R)-2-(2-bromo-6-fluoro-3-(oxiran-2-ylmethoxy)phenyl)-1,3-dioxolaneremained. The reaction mixture was quenched by the addition of water(500 mL) at 0° C. and extracted with EtOAc (100 mL*3). The combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to obtain(S)-(4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methanol(85 g, crude) as a yellow oil. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 7.05-6.91(m, 1H), 6.79 (dd, J=8.7, 3.9 Hz, 1H), 5.91 (s, 1H), 4.95 (t, J=5.3 Hz,1H), 4.62 (dd, J=8.8, 1.8 Hz, 1H), 4.42 (t, J=8.7 Hz, 1H), 4.15-4.07 (m,2H), 3.99-3.90 (m, 2H), 3.70-3.58 (m, 2H), 3.25-3.15 (m, 1H).

Example 8:(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloro-2-nitropyridine

The reaction was set up in to parallel batches. To a solution of(S)-(4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methanol(45.0 g, 187 mmol, 1.00 eq) and 5-bromo-6-chloro-2-nitropyridin-3-ol(41.8 g, 165 mmol, 0.88 eq) in toluenetoluene (1800 mL) was added PPh₃(73.7 g, 281 mmol, 1.50 eq). Then DIAD (45.5 g, 225 mmol, 43.7 mL, 1.20eq) was added to the mixture at 20° C. The mixture was stirred at 20° C.for 12 h. LCMS indicated that the reaction was complete. The two batcheswere combined. The mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 0/1; Petroleum ether/Ethyl acetate=2/1,R_(f)=0.72).(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloro-2-nitropyridine(300 g, crude) was obtained as yellow oil. ¹H NMR CDCl₃ 400 MHz, δ=ppm7.80 (s, 1H), 6.94 (dd, J=10.3, 8.8 Hz, 1H), 6.81 (dd, J=8.7, 4.0 Hz,1H), 6.05 (s, 1H), 4.75-4.70 (m, 1H), 4.54-4.46 (m, 2H), 4.20-4.15 (m,2H), 4.11-3.99 (m, 4H).

Example 9:(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloropyridin-2-amine

To a solution of(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloro-2-nitropyridine(150 g, 315 mmol, 1.00 eq) in AcOH (1250 mL) was added Fe (176 g, 3.15mol, 10.0 eq) at 20° C. The mixture was stirred at 35° C. for 2 h. LCMSshowed that the reaction was complete. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloropyridin-2-amine(90.0 g, crude) as a black oil.

Example 10:(R)-3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-carbaldehyde

To a solution of(R)-3-((4-(1,3-dioxolan-2-yl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)-5-bromo-6-chloropyridin-2-amine(90.0 g, 202 mmol, 1.00 eq) in THF (1000 mL) was added HCl (1.5 M, 240mL, 1.78 eq) at 20° C. The mixture was stirred at 20° C. for 10 h. Themixture was concentrated under reduced pressure. EtOAc (1000 mL) wasadded to the residue and the mixture was stirred at 20° C. for 10 mins.The mixture was filtered and the solid was washed with EtOAc (300 mL)and dried under reduced pressure. EtOAc (1000 mL) was added to theresidue and the pH was adjusted to 8-9 with sat. aq. NaHCO₃. The organiclayer was separated, washed with brine (300 mL), dried over Na₂SO₄, andfiltered. The filtrate was concentrated under reduced pressure to give(R)-3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-carbaldehyde(40.0 g, crude) as an off-white solid. ¹H NMR DMSO-Je 400 MHz, δ=ppm10.26 (s, 1H), 7.45-7.34 (m, 1H), 7.27-7.16 (m, 2H), 4.74 (brd, 7=8.2Hz, 1H), 4.61-4.50 (m, 1H), 4.23 (br s, 1H), 4.16 (br dd, J=9.5, 3.5 Hz,1H), 3.89-3.80 (m, 1H).

Example 11:(R)-(3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methanol

To a solution of(R)-3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-carbaldehyde(29.0 g, 72.2 mmol, 1.00 eq) in THF (300 mL) and MeOH (60 mL) was addedNaBH₄ (4.10 g, 108 mmol, 1.50 eq) at 25° C. The mixture was stirred at25° C. for 1 hr. LCMS showed the reaction was complete. The residue waspoured into water (400 mL) and stirred for 5 mins. The aqueous phase wasextracted with EtOAc (200 mL*2), dried with Na₂SO₄, filtered andconcentrated in vacuum.(R)-(3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methanol(32.0 g, crude) was obtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz,δ=ppm 7.42 (s, 1H), 7.02 (dd, J=10.2, 8.7 Hz, 1H), 6.78 (dd, J=8.6, 3.9Hz, 1H), 6.47 (br s, 2H), 5.39 (t, J=5.4 Hz, 1H), 4.75-4.67 (m, 2H),4.63-4.56 (m, 2H), 4.40 (dd, J=9.4, 4.2 Hz, 1H), 4.22-4.09 (m, 1H),4.03-3.95 (m, 1H).

Example 12:(R)-5-bromo-6-chloro-3-((4-(chloromethyl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)pyridin-2-amine

To a solution of(R)-(3-(((2-amino-5-bromo-6-chloropyridin-3-yl)oxy)methyl)-5-fluoro-2,3-dihydrobenzofuran-4-yl)methanol(30.0 g, 74.3 mmol, 1.00 eq) in THF (310 mL) was added SOCl₂ (13.3 g,111 mmol, 8.09 mL, 1.5 eq) at 20° C. The mixture was stirred at 20° C.for 1 hr. LCMS showed the reaction was complete. The mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1,Petroleum ether/Ethyl acetate=2/1, R_(f)=0.56).(R)-5-bromo-6-chloro-3-((4-(chloromethyl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)pyridin-2-amine(30.0 g, crude) was obtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz,δ=ppm 7.48-7.53 (br. m, 2H), 7.32 (s, 1H), 7.06 (t, J=9.6 Hz, 1H),6.82-6.85 (m, 1H), 4.82-4.84 (m, 2H), 4.62-4.64 (m, 2H), 4.28-4.31 (m,1H), 3.98-4.07 (m, 2H).

Example 13:(R)-10-bromo-9-chloro-5-fluoro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine

The reaction was set up in four parallel batches. To a solution of(R)-5-bromo-6-chloro-3-((4-(chloromethyl)-5-fluoro-2,3-dihydrobenzofuran-3-yl)methoxy)pyridin-2-amine(7.50 g, 17.8 mmol, 1.00 eq) in CH₃CN (1600 mL) was added Cs₂CO₃ (21.3g, 65.4 mmol, 3.67 eq) and TBAI (1.21 g, 3.27 mmol, 0.18 eq) at 20° C.The mixture was stirred at 65° C. for 3.5 h. The four batches werecombined and water (1000 mL) was added to the reaction mixture. Themixture was concentrated under reduced pressure to remove CH₃CN and theaqueous phase was extracted with EtOAc (500 mL*3). The combined organiclayers were washed with brine (500 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 2/1,Petroleum ether/Ethyl acetate=2/1, R_(f)=0.76).(R)-10-bromo-9-chloro-5-fluoro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine(12.0 g, 20.3 mmol, 47% yield) was obtained as a white solid. ¹H NMRCDCl₃ 400 MHz, δ=ppm 7.25 (s, 1H), 6.88-6.80 (m, 1H), 6.62 (dd, J=8.7,3.9 Hz, 1H), 5.36 (br t, J=7.8 Hz, 1H), 4.79 (dd, J=14.9, 9.2 Hz, 1H),4.65-4.55 (m, 2H), 4.49 (dd, J=14.8, 6.8 Hz, 1H), 4.21 (dd, J=9.5, 2.9Hz, 1H), 3.92-3.82 (m, 1H), 3.80-3.71 (m, 1H).

Example 14: tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a solution of(R)-10-bromo-9-chloro-5-fluoro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine(5.80 g, 15.0 mmol, 1.00 eq) in THF (90 mL) was added DMAP (441 mg, 3.61mmol, 0.24 eq), TEA (4.57 g, 45.1 mmol, 6.28 mL, 3.00 eq) and Boc₂O(19.70 g, 90.25 mmol, 20.73 mL, 6 eq) at 25° C. The mixture was stirredat 50° C. for 12 h. The reaction mixture was quenched by addition ofwater (50 mL) and extracted with EtOAc (30 mL*3). The combined organiclayers were washed with sat. NaCl (30 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1,Petroleum ether/Ethyl acetate=2:1, R_(f)=0.65). tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(6.60 g, 13.6 mmol, 90% yield) was obtained as a white solid. ¹H NMRCDCl₃ 400 MHz, δ=ppm 7.60 (s, 1H), 6.83 (t, J=9.4 Hz, 1H), 6.65 (dd,7=8.6, 3.7 Hz, 1H), 5.00-4.87 (m, 2H), 4.46-4.38 (m, 1H), 4.31 (br dd,J=11.0, 5.1 Hz, 1H), 4.18-4.14 (m, 1H), 4.12-4.08 (m, 1H), 3.94-3.81 (m,1H), 1.36 (s, 9H).

Example 15: tert-butyl(R)-10-bromo-5-fluoro-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

The reaction was set up in four parallel batches. To a solution oftert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(1.60 g, 3.29 mmol, 1.00 eq) in n-BuOH (60 mL) was added hydrazinehydrate (4.21 g, 82.4 mmol, 4.08 mL, 98% purity, 25 eq) at 25° C. Themixture was stirred at 100° C. for 12 h. The four batches were combinedand the resulting mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 0/1, Petroleum ether:Ethyl acetate=1:1,R_(f)=0.1). tert-butyl(R)-10-bromo-5-fluoro-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate (4.20 g, 8.73 mmol, 66% yield) was obtained as a whitesolid, tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(0.7 g, crude) was recovered as a yellow oil. ¹H NMR CDCl₃ 400 MHz,8=ppm 7.47 (s, 1H), 6.88-6.82 (m, 1H), 6.65 (dd, J=8.7, 3.8 Hz, 1H),6.06 (s, 1H), 5.11 (br d, J=15.7 Hz, 1H), 4.77 (br d, J=15.8 Hz, 1H),4.39 (t, J=8.9 Hz, 1H), 4.18-4.12 (m, 1H), 4.10-4.05 (m, 2H), 3.96-3.87(m, 2H), 1.33 (s, 9H).

Example 16: tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(R)-10-bromo-5-fluoro-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(4.20 g, 8.73 mmol, 1.00 eq) in CH(OEt)₃ (40.1 g, 271 mmol, 45.0 mL, 31eq) was added TFA (49.8 mg, 436 umol, 32.3 uL, 0.05 eq) at 25° C. Themixture was stirred at 100° C. for 3 h The reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1,Petroleum ether/Ethyl acetate=1/2, R_(f)=0.28). tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(4.20 g, 8.55 mmol, 97% yield) was obtained as a yellow solid. ¹H NMRCDCl₃ 400 MHz, δ=ppm 8.70 (br s, 1H), 7.30-7.27 (m, 1H), 6.70-6.55 (m,2H), 5.31 (br s, 1H), 4.78-4.54 (m, 2H), 4.53-4.45 (m, 1H), 4.27 (d,J=9.8 Hz, 1H), 4.03-3.83 (m, 2H), 1.34 (br s, 9H).

Example 17:(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(2.50 g, 5.09 mmol, 1.00 eq) was added HFIP (25 mL) at 25° C. Themixture was stirred at 100° C. for 12 h The reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1,Petroleum ether:Ethyl acetate=0:1, R_(f)=0.10).(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(1.60 g, 4.09 mmol, 80% yield) was obtained as a white solid. ¹H NMRDMSO-d₆ 400 MHz, δ=ppm 9.46 (s, 1H), 7.68 (s, 1H), 7.50 (br t, J=6.4 Hz,1H), 6.97-6.89 (m, 1H), 6.67 (dd, J=8.6, 3.9 Hz, 1H), 4.88-4.69 (m, 2H),4.57-4.38 (m, 2H), 4.19 (dd, J=9.5, 3.5 Hz, 1H), 4.01-3.94 (m, 1H),3.89-3.78 (m, 1H).

Example 18:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)propan-2-olStep 1: tert-butyl(S)-4-(6-acetylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 204 umol, 1.00 eq) in dioxane (5 mL) and water (0.5 mL) wasadded1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-1-one(65.4 mg, 265 umol, 1.3 eq), NaHCO₃ (85.5 mg, 1.02 mmol, 39.6 uL, 5.00eq) and Pd(dppf)Cl₂ (14.9 mg, 20.4 umol, 0.100 eq) at 20° C. undernitrogen atmosphere, the mixture was stirred at 80° C. for 12 h. Thereaction was concentrated under the reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).Tert-butyl(S)-4-(6-acetylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 151 umol, 73% yield) was obtained as a yellow oil.

Step 2:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)propan-2-olformate salt

To a solution of tert-butyl(S)-4-(6-acetylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(70.0 mg, 132 umol, 1.00 eq) in toluene (4 mL) was addedtrimethylalumane (2 M, 217 uL, 3.3 eq) at 20° C., the mixture wasstirred at 50° C. for 12 h. LC-MS showed tert-butyl(S)-4-(6-acetylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and the desired mass was detected. Water (3 mL)was added to the mixture, the mixture was the mixture was extracted withethyl acetate (5 mL*3), the combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby prep-HPLC (column: Nano-micro Kromasil C18 100*30 mm 5 um; mobilephase: [water (0.225% FA)-ACN]; B %: 10%-45%, 12 min).(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)propan-2-ol(25.0 mg, 50.6 umol, 38% yield, 99.9% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz, 8=ppm 9.44 (s, 1H), 9.19 (s,1H), 8.49 (dd, 7=8.5, 1.9 Hz, 1H), 7.76-7.65 (m, 2H), 7.58 (br t, J=5.8Hz, 1H), 6.94 (br t, J=9.6 Hz, 1H), 6.67 (dd, J=8.5, 3.6 Hz, 1H), 5.25(s, 1H), 4.97-4.71 (m, 2H), 4.60-4.43 (m, 2H), 4.30-4.14 (m, 1H),4.09-3.85 (m, 2H), 1.46 (s, 6H). LCMS (ESI+): m/z 448.2 (M+H)

Example 19: General Procedure D. Preparation of(S)-12-fluoro-4-(4-(methylsulfonyl)phenyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(55.0 mg, 141 umol, 1.00 eq) and4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane(51.6 mg, 183 umol, 1.3 eq) in dioxane (1 mL) and water (0.1 mL) wereadded Pd(dppf)Cl₂ (10.3 mg, 14.1 umol, 0.100 eq) and NaHCO₃ (59.1 mg,703 umol, 27.3 uL, 5.00 eq) at 20° C. The mixture was degassed andpurged with nitrogen 3 times, then stirred at 80° C. for 3 h undernitrogen atmosphere. Reaction progress was monitored by LC-MS. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure to give a crude product. The crude product was purifiedby prep-HPLC (neutral condition).(S)-12-fluoro-4-(4-(methylsulfonyl)phenyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(12.7 mg, 26.3 umol, 18% yield, 96.7% purity) was obtained as a yellowsolid. ¹H NMR DMSO-de 400 MHz, δ=ppm 9.48 (s, 1H), 8.52 (d, J=8.6 Hz,2H), 7.97 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.77 (br s, 1H), 6.99-6.92(m, 1H), 6.69 (dd, J=8.6, 3.7 Hz, 1H), 4.97-4.86 (m, 1H), 4.86-4.76 (m,1H), 4.54 (br t, J=9.2 Hz, 2H), 4.21 (dd, J=9.6, 3.2 Hz, 1H), 4.11-4.01(m, 1H), 3.97 (br d, J=10.8 Hz, 1H), 3.25 (s, 3H). LCMS (ESI+): m/z467.1 (M+H).

Compounds 22 and 30 were prepared according to General Procedure D usingthe suitable starting materials, precursors, intermediates, andreagents.

Cmpd No. Compound Name Structure Spectral Data 22 (S)-4-(1,3-dimethyl-1H- pyrazol-4-y1)-12- fluoro- 7a,8,13,14- tetrahydro-7H-[1,2,4]triazolo[4',3':1,6] pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR CDCl₃ 400 MHz, δ = ppm 8.74 (s, 1H), 8.48 (s, 1H), 7.17 (s, 1H),6.89-6.79 (m, 1H), 6.64 (dd, J = 8.7, 4.1 Hz, 1H), 5.04 (hr dd, J =14.8, 7.7 Hz, 1H), 4.80 (hr dd, J = 14.6, 6.0 Hz, 1H), 4.65-4.58 (m,2H), 4.47 (hr s, 1H), 4.26 (dd, J = 9.8, 2.5 Hz, 1H), 3.89 (s, 3H),3.88-3.81 (m, 1H), 2.49 (s, 3H). LCMS (ESI+): m/z 407.1 (M + H). 30(S)-12-fluoro-4-(2- methoxypyrimidin-5- y1)-7a,8,13,14- tetrahydro-7H-[1,2,4]triazolo[4',3':1,6] pyrido[3,2- b]benzofuro[4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz, δ = ppm 9.47 (s, 1H), 9.38 (s, 2H), 7.85 (s,1H), 7.67- 7.62 (m, 1H), 6.96 (t, J = 9.6 Hz, (dd, J = 8.4, 3.6 Hz, 1H),4.94-4.87 (m, 1H), 4.81 (hr s, 1H), 4.58-4.50 (m, 2H), 4.22 (hr d, J =9.2 Hz, 1H), 4.04 (hr s, 1H), 3.98 (s, 3H), 3.97-3.91 (m, 1H). LCMS(ESI+): m/z 421.2 (M + H).

Example 20:(S)-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-6-chloro-2-nitro-pyridin-3-ol

5-Bromo-6-chloro-pyridin-3-ol (5.00 g, 24.0 mmol) was added portion-wiseto concentrated H₂SO₄ (15.0 mL) at 0° C. After 75 min, a mixture ofcone. H₂SO₄ (98%) and fuming nitric acid (4.00 mL, 2.50/1.50 (v/v)) wasadded over 5 min with a dropping funnel under vigorous stirring. Afterstirring for 2 h at 0° C., the mixture was warmed to room temperaturefor 16 h. The mixture was slowly poured into 300 g of ice-water (2/1),and the mixture was stirred for 1 h. The mixture was filtered through aBuchner funnel, and the filter cake was washed with water (3×150 mL).The solid was dissolved in EtOAc (50 mL), and the organic phase waswashed with brine (15 mL). The organic layer was dried (MgSO₄),filtered, and concentrated under reduced pressure to afford5-bromo-6-chloro-2-nitro-pyridin-3-ol as a solid (3.98 g, 65%). ¹H NMRDMSO 500 MHz, δ 8.02 (s, 1H).

Step 2: 2-bromo-3-(1,3-dioxolan-2-yl) phenol

p-Toluenesulfonic acid (857 mg, 4.98 mmol) was added to a solution of2-bromo-3-hydroxy-benzaldehyde (10.0 g, 49.8 mmol) and ethylene glycol(13.9 mL, 249 mmol) in toluene (225 mL). The mixture was stirred for 5 hat reflux. The mixture was cooled to room temperature and concentratedto a third of the initial volume. The residual solution was diluted witha saturated NaHCO₃ solution (150 mL), and the aqueous phase wasextracted with EtOAc (3×75 mL). The combined organic layers were washedwith brine (150 mL), dried (MgSO₄), filtered, and concentrated toprovide 2-bromo-3-(1,3-dioxolan-2-yl) phenol as an oil (8.53 g, 70%). ¹HNMR CDCl₃ 500 MHz, δ 7.29-7.23 (m, 1H), 7.20-7.16 (m, 1H), 7.06 (dd,J=8.0, 1.7 Hz, 1H), 6.08 (s, 1H), 5.88 (s, 1H), 4.22-4.13 (m, 2H),4.13-4.06 (m, 2H).

Step 3: 2-[2-bromo-3-[[(2R)-oxiran-2-yl]methoxy]phenyl]-1,3-dioxolane

CsF (10.6 g, 69.6 mmol) was added to a solution of2-bromo-3-(1,3-dioxolan-2-yl) phenol (8.53 g, 34.8 mmol) in dry DMF (160mL). The mixture was stirred for 1 hour at room temperature.[(2R)-Oxiran-2-yl] methyl 3-nitrobenzenesulfonate (9.02 g, 34.8 mmol)was added, and the mixture was stirred for 18 h. Water (250 mL) wasadded, and the aqueous phase was extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with water (2×300 mL) and brine (250mL), dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (120 gcartridge) eluting with EtOAc in hexanes (30-80%) to provide2-[2-bromo-3-[[(2R)-oxiran-2-yl]methoxy]phenyl]-1,3-dioxolane as an oil(6.11 g, 58%). ¹H NMR CDCl₃400 MHz, δ 7.28 (t, J=7.7 Hz, 1H), 7.24 (dd,J=7.8, 1.9 Hz, 1H), 6.94 (dd, J=7.7, 1.9 Hz, 1H), 6.16 (s, 1H), 4.29(dd, J=11.2, 3.1 Hz, 1H), 4.15-4.12 (m, 1H), 4.11-4.04 (m, 4H),3.43-3.35 (m, 1H), 2.91 (dd, J=5.0, 4.2 Hz, 1H), 2.86 (dd, J=5.0, 2.6Hz, 1H).

Step 4: [(3S)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methanol

n-BuLi (8.93 mL, 22.3 mmol, 2.50 M in hexanes) was added drop wise to asolution of2-[2-bromo-3-[[(2R)-oxiran-2-yl]methoxy]phenyl]-1,3-dioxolane (6.11 g,20.3 mmol) in THF (100 mL) at −78° C. The mixture was warmed to roomtemperature over 3 h. A saturated NH₄Cl solution (100 mL) was added. Theaqueous phase was extracted with EtOAc (3×100 mL), and the combinedorganic layers were washed with brine (100 mL), dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (120 g cartridge) eluting withEtOAc in hexanes (0-100%) to provide[(3S)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl] methanol as asolid (1.93 g, 43%). ¹H NMR CDCl₃400 MHz, δ 7.19 (t, J=7.8 Hz, 1H), 7.05(dd, J=7.7, 0.9 Hz, 1H), 6.84 (dd, J=8.0, 0.9 Hz, 1H), 5.87 (s, 1H),4.62-4.49 (m, 2H), 4.24-4.11 (m, 2H), 4.10-4.01 (m, 2H), 3.85-3.68 (m,3H), 2.33 (t, J=6.1 Hz, 1H). m/z (ES+) [M+H]⁺: 223.0; HPLC t_(R)(B05)=1.39 min.

Step 5:3-bromo-2-chloro-5-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-6-nitro-pyridine

DIAD (1.92 mL, 9.77 mmol) was added drop wise to a solution of5-bromo-6-chloro-2-nitro-pyridin-3-ol (2.19 g, 8.64 mmol),[(3S)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methanol (1.81 g,8.14 mmol), and PPh₃ (3.20 g, 12.2 mmol) in toluene (60.0 mL) at roomtemperature. The mixture was stirred at room temperature for 20 h andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (120 g cartridge) eluting with EtOAc in hexanes(0-60%) to afford the title compound, which was further purified byreverse phase column chromatography (C-18, 80 g cartridge) eluting withwater (0.5% formic acid added)/ACN to provide3-bromo-2-chloro-5-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-6-nitro-pyridineas a solid (3.38 g, 91%), ¹H NMR CDCl₃ 500 MHz, δ 7.85 (s, 1H), 7.23 (t,J=7.9 Hz, 1H), 7.06-7.02 (m, 1H), 6.87 (d, J=8.0 Hz, 1H), 5.85 (s, 1H),4.71 (dd, J=9.4, 1.8 Hz, 1H), 4.55-4.48 (m, 2H), 4.19-4.12 (m, 2H),4.12-4.06 (m, 2H), 4.06-3.96 (m, 2H). m/z (ES+) [M+H]⁺: 458.86; HPLCt_(R) (B05)=2.11 min.

Step 6:5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]pyridin-2-amine

Fe (3.74 g, 67.0 mmol) was added in portions to a suspension of3-bromo-2-chloro-5-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-6-nitro-pyridine(3.07 g, 6.70 mmol) in HOAc (60.0 mL) at room temperature. The mixturewas stirred at room temperature for 2 h. The mixture was filteredthrough a pad of Celite. The Celite was washed with EtOAc (3×50 mL), andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (40.0 g cartridge) eluting withEtOAc in hexanes (0-70%) to afford5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]pyridin-2-amineas a solid (2.39 g, 84%), ¹H NMR CDCl₃ 500 MHz, δ 7.23 (t, J=7.9 Hz,1H), 7.14 (s, 1H), 7.05 (d, J=7.7 Hz, 1H), 6.87 (dd, J=8.0, 0.7 Hz, 1H),5.88 (s, 1H), 4.81 (s, 2H), 4.66 (dd, J=9.2, 1.8 Hz, 1H), 4.58-4.49 (m,1H), 4.34-4.23 (m, 1H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 4.04-3.97(m, 2H); m/z (ES+) [M+H]⁺: 429.16; HPLC t_(R) (B05)=2.02 min.

Step 7:N-[5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide

2-Nitrobenzenesulfonyl chloride (3.71 g, 16.7 mmol) was added to astirred solution of5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]pyridin-2-amine(1.59 g, 3.72 mmol) in pyridine (50.0 mL) at room temperature. Themixture was heated to 60° C. for 24 h. The mixture was concentrated, andwater (30 mL) was added to the residue. The mixture was filtered througha Buchner funnel, and the solid was washed with water (100 mL). Thesolid was diluted in sat. NaHCO₃ (30 mL) and EtOAc (30 mL). The aqueousphase was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (120 g cartridge) eluting with EtOAc in hexanes(0-60%) to afford the mono-Ns protected product as a solid (657 mg,29%). m/z (ES+) [M+H]⁺: 613.93, HPLC t_(R) (A05)=2.10 min (see step 8)and the bis-Ns protected product as a solid (1.04 g, 35%), NMR CDCl₃ 500MHz, δ 8.64 (dd, J=7.9, 1.5 Hz, 1H), 8.62-8.58 (m, 1H), 7.89-7.80 (m,4H), 7.73 (s, 1H), 7.72-7.65 (m, 2H), 7.19 (t, J=7.9 Hz, 1H), 6.98 (d,J=7.4 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 5.74 (s, 1H), 4.31 (dd, J=9.2,2.7 Hz, 1H), 4.19 (dd, J=9.4, 2.2 Hz, 1H), 4.17-4.09 (m, 3H), 4.08-4.02(m, 2H), 3.73 (dd, J=11.0, 9.2 Hz, 1H), 3.57-3.48 (m, 1H); m/z (ES+)[M+H]⁺:798.64, HPLC t_(R) (A05)=2.18 min.

Step 8:N-[5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide

PhSH (27.9 μL, 0.263 mmol) and Cs₂CO₃ (85.7 mg, 0.263 mmol) were addedto a solution of3-bromo-2-chloro-5-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-6-nitropyridine (210 mg, 0.263 mmol) in MeCN (15.0 mL) at room temperature. Themixture was stirred at room temperature for 3 h. The mixture was dilutedwith sat. aq. NaHCO₃ (10 mL) and EtOAc (30 mL). The aqueous phase wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (25 mL), dried over MgSO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography (12 g, cartridge)eluting with EtOAc in hexanes (0-70%) to affordN-[5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamideas a solid (125 mg, 78%). ¹H NMR CDCl₃ 500 MHz, δ 8.59 (dd, J=7.8, 1.1Hz, 1H), 8.39 (s, 1H), 7.81-7.73 (m, 3H), 7.33 (s, 1H), 7.24 (t, J=8.0Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 5.97 (s, 1H),4.63-4.55 (m, 2H), 4.30 (dd, J=8.7, 5.1 Hz, 1H), 4.18-4.10 (m, 4H),4.08-4.05 (m, 1H), 4.00 (t, J=8.7 Hz, 1H); m/z (ES+) [M+H]⁺: 613.56,HPLC t_(R) (B05)=1.78 min.

Step 9:N-[5-bromo-6-chloro-3-[[(3R)-4-formyl-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide

Aqueous HCl (10.5 mL, 10.5 mmol, 1.00 M) was added to a solution ofN-[5-bromo-6-chloro-3-[[(3R)-4-(1,3-dioxolan-2-yl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide(1.28 g, 2.09 mmol) in THF (25.0 mL) at room temperature. The mixturewas stirred at room temperature for 18 h. A saturated NaHCO₃ solution (8mL) was added, and the aqueous phase was extracted with EtOAc (3×25 mL).The combined organic extracts were washed with brine (15 mL), dried overMgSO₄, filtered, and concentrated to affordN-[5-bromo-6-chloro-3-[[(3R)-4-formyl-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamideas a solid (1.18 g, 99%), which was used as such in next step withoutpurification, m/z (ES+) [M+H]⁺: 569.91, HPLC t_(R) (A05)=2.16 min.

Step 10:N-[5-bromo-6-chloro-3-[[(3R)-4-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide

NaBH₄ (0.118 g, 3.13 mmol) was added in portions to a mixture of3-[(2-amino-5-bromo-6-chloro-3-pyridyl)oxymethyl]-2,3-dihydrobenzofuran-4-carbaldehyde (1.19 g, 2.08 mmol) inTHF (15.0 mL) and MeOH (3.00 mL) at room temperature. The mixture wasstirred at room temperature for 2 h. The mixture was diluted with sat.NH₄Cl (8.00 mL), water (10.0 mL), and EtOAc (30.0 mL). The aqueous phasewas extracted with EtOAc (4×25.0 mL). The combined organic layers werewashed with brine (30 mL), dried (MgSO₄), filtered, and concentrated.The residue was purified by silica gel chromatography (40 g, cartridge)with EtOAc in Hexanes (0-60%) to affordN-[5-bromo-6-chloro-3-[[(3R)-4-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamideas a solid (877 mg, 74%). ¹H NMR CDCl₃500 MHz, δ 8.60 (d, J=7.8 Hz, 1H),7.77 (d, J=7.6 Hz, 1H), 7.73 (s, 2H), 7.30 (s, 1H), 7.22 (t, J=7.8 Hz,1H), 6.90 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 4.82 (dd, J=27.5,12.3 Hz, 2H), 4.60 (dd, J=9.4, 7.5 Hz, 1H), 4.56-4.48 (m, 1H), 4.23 (t,J=7.1 Hz, 1H), 4.09-3.99 (m, 2H); m/z (ES+) [M+H]⁺: 571.59, HPLC t_(R)(B05)=1.71 min.

Step 11:(R)-10-bromo-9-chloro-7-((2-nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine

A solution of DIAD (0.398 mL, 2.02 mmol) in toluene (40.0 mL) was addeddrop wise over 1 h to a stirred solution ofN-[5-bromo-6-chloro-3-[[4-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl]methoxy]-2-pyridyl]-2-nitro-benzenesulfonamide(770 mg, 1.35 mmol) and PPh₃ (637 mg, 2.43 mmol) in toluene (300 mL) atroom temperature. The mixture was stirred at room temperature for 15 hand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (80 g, cartridge) with EtOAc in hexanes(0-50%) to provide(R)-10-bromo-9-chloro-7-((2-nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonineas a solid (600 mg, 81%). ¹H NMR CDCl₃500 MHz, δ 8.42-8.35 (m, 1H),7.79-7.73 (m, 3H), 7.42 (s, 1H), 7.04 (t, J=7.9 Hz, 1H), 6.86 (d, J=7.8Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 5.28 (d, J=13.3 Hz, 1H), 5.08 (d,J=13.3 Hz, 1H), 4.69 (dd, J=10.6, 5.5 Hz, 1H), 4.50 (dd, J=9.6, 8.2 Hz,1H), 4.23 (dd, J=9.7, 2.0 Hz, 1H), 4.07-3.98 (m, 1H), 3.90 (t, J=11.1Hz, 1H); ¹³C NMR CDCl₃ 125 MHz, 159.71, 149.69, 148.38, 141.65, 141.11,134.71, 134.60, 133.89, 133.76, 132.27, 131.64, 130.04, 127.65, 123.87,122.62, 117.39, 109.80, 78.11, 72.09, 50.99, 40.87; m/z (ES+) [M+H]⁺:553.44, HPLC t_(R) (B05)=2.42 min.

Step 12:(R)-10-bromo-9-chloro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine

PhSH (0.0187 mL, 0.176 mmol) and Cs₂CO₃ (0.115 g, 0.353 mmol) were addedto a solution of provide(R)-10-bromo-9-chloro-7-((2-nitrophenyl)sulfonyl)-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine(65.0 mg, 0.118 mmol) in MeCN (1.00 mL) at room temperature. The mixturewas stirred at room temperature for 3 h. The mixture was diluted withsat. NaHCO₃ (10 mL) and EtOAc (10 mL). Water (10 mL) was added. Theaqueous phase was extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine (15 mL), dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (12 g, cartridge) eluting with EtOAc in hexanes(0-70%) to afford(R)-10-bromo-9-chloro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonineas a solid (43.0 mg, 99%). ¹H NMR CDCl₃ 500 MHz, δ 7.29 (s, 1H), 7.14(t, J=7.8 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 5.35(t, J=7.8 Hz, 1H), 4.70 (dd, J=15.1, 8.5 Hz, 1H), 4.54 (t, J=9.2 Hz,2H), 4.46 (dd, J=9.5, 3.9 Hz, 1H), 4.17 (dd, J=9.6, 3.2 Hz, 1H), 3.95(ddd, J=12.5, 8.4, 3.7 Hz, 1H), 3.90-3.79 (m, 1H). m/z (ES+) [M+H]⁺:368.97; HPLC t_(R) (B05)=2.73 min.

Step 13

Boc anhydride (4.05 mL, 17.6 mmol) was added to a solution of(R)-10-bromo-9-chloro-6,7,13,13a-tetrahydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine(1.08 g, 2.94 mmol), TEA (1.23 mL, 8.82 mmol), and DMAP (90.0 mg, 0.735mmol) in THF (50.0 mL). The mixture was stirred at 50° C. for 8 h. Water(40 mL) was added, and the aqueous phase was extracted with EtOAc (3×75mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (40 g cartridge)eluting with EtOAc in hexanes (30-80%) to provide tert-butyl(R)-10-bromo-9-chloro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylateas a solid (1.37 g, 99%). ¹H NMR CDCl₃ 400 MHz, δ 7.52 (s, 1H), 7.06 (t,J=7.8 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 4.92 (d,J=14.6 Hz, 1H), 4.74 (d, J=14.5 Hz, 1H), 4.42-4.33 (m, 2H), 4.15 (dd,J=9.5, 2.0 Hz, 1H), 4.01 (t, J=11.3 Hz, 1H), 3.81-3.72 (m, 1H), 1.35 (s,9H). m/z (ES+) [M-Boc]⁺: 367.6; HPLC t_(R) (B05)=2.87 min.

Step 14: tert-butyl(R)-10-bromo-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

Hydrazine monohydrate (0.519 mL, 10.7 mmol) was added to a solution oftert-butyl(R)-10-bromo-9-chloro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate (0.200 g, 0.428 mmol) in EtOH (10.0 mL). The mixturewas heated to 100° C. for 72 h. After cooling to room temperature, themixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (24 g cartridge) with MeOH in DCM(0-10%) to afford tert-butyl(R)-10-bromo-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylateas a solid (178 mg, 90%). m/z (ES+) [M]⁺: 463.77, HPLC t_(R) (B05)=2.59min.

Step 15: tert-butyl(S)-4-bromo-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(R)-10-bromo-9-hydrazineyl-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(330 mg, 0.712 mmol), triethyl orthoformate (21.3 mL, 128 mmol), and TFA(2.70 uL, 0.0356 mmol) was heated to 100° C. for 1 h. After cooling toroom temperature, the mixture was concentrated, and the residue waspurified by silica gel chromatography (24 g) with MeOH in DCM (0-10%) toafford tert-butyl(S)-4-bromo-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (315 mg, 93%). m/z (ES+) [M]⁺: 473.74; HPLC t_(R) (B05)=2.51min.

Step 16:(S)-4-bromo-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl tert-butyl(S)-4-bromo-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.110 g, 0.232 mmol) in HFIP (5.00 mL) was heated to 100° C. in an oilbath for 3 h. The mixture was concentrated under reduced pressure, andthe residue was purified by silica gel chromatography (12 g) with MeOHin DCM (0-20%) to afford(S)-4-bromo-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineas a solid (44.0 mg, 51%). ¹H NMR CD₃OD 400 MHz, δ 9.24 (s, J=15.5 Hz,1H), 7.61 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.61(d, J=7.9 Hz, 1H), 4.48 (t, J=9.4 Hz, 1H), 4.42 (dd, J=10.4, 4.4 Hz,1H), 4.16 (dd, J=9.6, 3.6 Hz, 1H), 4.01-3.91 (m, J=13.1, 8.4, 4.0 Hz,1H), 3.86-3.77 (m, 1H), 2.24 (t, J=7.4 Hz, 1H), 1.33-1.27 (m, 1H). m/z(ES+) [M]⁺: 373.80; HPLC t_(R) (B05)=2.35 min.

Step 17:(S)-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Dioxane (3.00 mL) and water (0.600 mL) were sequentially added to amixture of(S)-4-bromo-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(44.0 mg, 0.118 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (31.0mg, 0.141 mmol), Pd(dppf)Cl₂ (8.63 mg, 0.0118 mmol), and NaHCO₃ (49.5mg, 0.589 mmol) under N₂. The mixture was heated to 90° C. for 2 h. Themixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (12 g cartridge) eluting with MeOHin DCM (0-30%) and further purified by HPLC (BEH 30×100 mm ACN/AmForm31-51%) to afford(S)-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineas a solid (30.0 mg, 66%). ¹H NMR DMSO 400 MHz, δ 9.38 (s, 1H), 8.47(dd, J=4.8, 1.7 Hz, 1H), 7.76 (dd, J=7.7, 1.7 Hz, 1H), 7.52 (t, J=6.5Hz, 1H), 7.31 (s, 1H), 7.29 (dd, J=7.7, 4.9 Hz, 1H), 7.13 (t, J=7.8 Hz,1H), 6.91 (d, J=7.5 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 4.87-4.74 (m, 2H),4.51 (t, J=9.5 Hz, 1H), 4.47-4.39 (m, 1H), 4.16 (dd, J=9.6, 3.8 Hz, 1H),4.07-3.96 (m, 1H), 3.83 (t, J=11.4 Hz, 1H), 2.36 (s, 3H). m/z (ES+)[M+H]⁺: 386.91; HPLC t_(R) (B05)=2.30 min.

Example 21:(S)-1-(4-(7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneStep 1:(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas synthesized according to Example 20, step 15.

Step 2: tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Dioxane (2.00 mL), water (0.400 mL), and NaHCO₃ (0.634 mmol, 53.2 mg)were added to a mixture of tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.127 mmol, 60.0 mg),1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(0.133 mmol, 33.3 mg), and Pd(dppf)Cl₂ (0.0127 mmol, 9.28 mg) under N₂.The mixture was heated to 100° C. for 2 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure, andthe residue was purified by silica gel chromatography (12 g cartridge)eluting with MeOH in DCM (0-30%) to tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (63.0 mg, 96%). m/z (ES+) [M+H]⁺: 518.8; HPLC t_(R)(B05)=2.42 min.

Step 3: tert-butyl(S)-4-(1-acetylpiperidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

MeOH (10.00 mL) was added to a mixture of tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.122 mmol, 63.0 mg) and Pd/C (10.0%, 24.3 μmol, 25.9 mg) at roomtemperature. The reaction vessel was evacuated and purged with H₂. Thesolution was stirred at rt for 12 h. The mixture was filtered overCelite, and the Celite pad was washed with DCM (3×15 mL). The filtratewas concentrated under reduced pressure. The residue was used as such inthe next step without further purification (63 mg, quant.), m/z (ES+)[M+H]⁺: 520.97. HPLC t_(R) (B05)=2.36 min.

Step 4:(S)-1-(4-(7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one

A solution of tert-butyl(S)-4-(1-acetylpiperidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.121 mmol, 63.0 mg) in HFIP (2.00 mL) was heated to 100° C. for 3 h.The mixture was concentrated under reduced pressure, and the residue waspurified by HPLC (BEH 30×100 mm ACN/AmBicarb, 27-47%) to afford(S)-1-(4-(7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneas a solid (32.0 mg, 63%). ¹H NMR DMSO 500 MHz, δ 9.29 (s, 1H), 7.18 (t,J=6.7 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J=7.6 Hz,1H), 6.64 (d, J=7.8 Hz, 1H), 4.75 (dd, J=14.7, 6.4 Hz, 1H), 4.69-4.59(m, 1H), 4.57-4.50 (m, 1H), 4.48 (t, J=9.4 Hz, 1H), 4.45-4.38 (m, 1H),4.16 (dd, J=9.6, 3.5 Hz, 1H), 4.00-3.87 (m, 2H), 3.74 (td, J=11.7, 3.7Hz, 1H), 3.25-3.10 (m, 2H), 2.66-2.56 (m, 1H), 2.02 (d, J=3.8 Hz, 3H),1.97-1.82 (m, 2H), 1.82-1.67 (m, 1H), 1.67-1.53 (m, 1H). m/z (ES+)[M+H]⁺: 420.8; HPLC t_(R) (B05)=2.22 min.

Example 22:12-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazoninehydrochloride hydrochloride Step 1: methyl 2-bromo-6-fluoro-benzoate

2-Bromo-6-fluorobenzoic acid (12.5 g, 57.1 mmol) was dissolved in amixture of MeOH (60.0 mL) and concentrated sulfuric acid (60.0 mL). Thesolution was heated to 80° C. for 12 h. The mixture was slowly added tosolution of aq. sodium carbonate solution (20%, 500 mL) at 0° C. Theaqueous phase was extracted with DCM (3×175 mL), and the combinedorganic layers were dried (MgSO₄), filtered, and concentrated underreduced pressure to provide methyl 2-bromo-6-fluoro-benzoate as an oil(7.06 g, 53%). ¹H NMR CDCl₃ 500 MHz, δ 7.40 (dt, J=8.1, 0.8 Hz, 1H),7.27 (dd, J=14.1, 8.3 Hz, 1H), 7.09 (td, J=8.6, 1.0 Hz, 1H), 3.97 (s,3H).

Step 2: methyl 2-allyl-6-fluoro-benzoate

Dioxane (50.0 mL) and water (12.5 mL) were sequentially added to amixture of methyl 2-bromo-6-fluoro-benzoate (5.00 g, 21.5 mmol), K₂CO₃(9.00 g, 65.1 mmol), and Pd(dppf)Cl₂ (1.50 g, 2.05 mmol) under nitrogen.2-Allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.04 mL, 32.2 mmol) wasadded, and the mixture was heated to 90° C. for 24 h. The mixture wasdiluted with DCM (150 mL), filtered (Celite), and the filtrated wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (40 g, cartridge) with a gradient of EtOAc in hexanes(0-100%) to afford methyl 2-allyl-6-fluoro-benzoate as an oil (2.12 g,51%). ¹H NMR CDCl₃ 500 MHz, δ 7.40-7.32 (m, 1H), 7.06 (d, J=7.7 Hz, 1H),7.00 (t, J=8.9 Hz, 1H), 5.93 (ddt, J=16.8, 10.1, 6.6 Hz, 1H), 5.08 (tq,J=17.2, 1.6 Hz, 2H), 3.94 (s, 3H), 3.51 (d, J=6.6 Hz, 2H).

Step 3: (2-Allyl-6-fluoro-phenyl) methanol

DIBAL-H (30.0 mL, 30.0 mmol) was added to a solution of methyl2-allyl-6-fluoro-benzoate (2.10 g, 10.8 mmol) in THF (40.0 mL) at 0° C.The mixture was stirred at room temperature for 14 h. Water (1.60 mL)was added drop wise at 0° C., followed by NaOH (1.60 mL, 1.00 M) andadditional water (1.60 mL). The mixture was stirred at room temperaturefor 1 h and filtered through Celite, washing with Et₂O (150 mL). Thefiltrate was concentrated under reduced pressure, and the residue wasused as such without further purification (1.79 g, >99%). ¹H NMR CDCl₃500 MHz, δ 7.23 (td, J=8.0, 5.9 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.96(t, J=9.0 Hz, 1H), 6.02 (ddt, J=16.3, 10.1, 6.2 Hz, 1H), 5.10 (dq,J=10.1, 1.6 Hz, 1H), 5.01 (dq, J=17.1, 1.7 Hz, 1H), 4.76 (dd, J=6.3, 1.8Hz, 2H), 3.55 (dt, J=6.2, 1.5 Hz, 2H).

Step 4: (2-Allyl-6-fluoro-phenyl) methoxy-triisopropyl-silane

TIPS-Cl (3.52 mL, 16.4 mmol) was added to a solution of(2-allyl-6-fluoro-phenyl) methanol (2.10 g, 12.6 mmol), imidazole (2.58g, 37.9 mmol), and DMAP (30.0 mg, 0.246 mmol) in DCM (36.0 mL) at rtunder nitrogen. The mixture was stirred at rt for 18. The solution wasdiluted with water (125 mL), and the aqueous phase was extracted withEt₂O (125 mL) and hexanes (2×50.0 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (40 g, cartridge) witha gradient of EtOAc in hexanes (0-100%) to afford(2-Allyl-6-fluoro-phenyl) methoxy-triisopropyl-silane as an oil (3.97 g,97%). ¹H NMR CDCl₃ 400 MHz, δ 7.19-7.13 (m, 1H), 6.96 (d, J=7.6 Hz, 1H),6.87 (t, J=9.0 Hz, 1H), 5.97 (ddt, J=16.6, 10.1, 6.4 Hz, 1H), 5.01 (tq,J=17.0, 1.7 Hz, 2H), 4.81 (d, J=2.0 Hz, 2H), 3.57 (dt, J=6.4, 1.4 Hz,2H), 1.20-1.07 (m, 3H), 1.06-1.00 (m, 18H).

Step 5: 2-[3-Fluoro-2-(triisopropylsilyloxymethyl) phenyl] acetaldehyde

NaIO₄ (10.5 g, 49.2 mmol) was added to a stirred solution of OsO₄(4.00%, 0.500 mL, 0.0787 mmol) and (2-allyl-6-fluoro-phenyl)methoxy-triisopropyl-silane (3.97 g, 12.3 mmol) in a mixture of1,4-dioxane (50.0 mL) and water (16.0 mL) under N₂. The mixture wasstirred at rt for 12 h. Sat. aq. Na₂SO₃ (100 mL) was added, and theaqueous phase was extracted with EtOAc (3×100 mL). The combined organicphases were washed with sat. aq. NaHCO₃ (100 mL), dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue was usedas such without further purification. ¹H NMR CDCl₃ 500 MHz, δ 9.74 (t,J=1.9 Hz, 1H), 7.30-7.20 (m, 1H), 7.03-6.96 (m, 2H), 4.84 (d, J=1.9 Hz,2H), 3.90 (d, J=1.9 Hz, 2H), 1.17-1.11 (m, 3H), 1.05 (s, 18H).

Step 6: 2-[3-Fluoro-2-(triisopropylsilyloxymethyl)phenyl]ethanol

NaBH₄ (700 mg, 18.5 mmol) was added to a solution of2-[3-fluoro-2-(triisopropylsilyloxymethyl) phenyl] acetaldehyde (3.98 g,12.3 mmol) in THF (60.0 mL) and MeOH (20.0 mL) at 0° C. The mixture waswarmed to room temperature and stirred for 1 h. The mixture was dilutedwith sat. NH₄Cl (10 mL), water (100 mL), and EtOAc (200 mL). The mixturewas stirred at room temperature for 30 min. The aqueous phase wasextracted with EtOAc (2×200 mL). The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (24 g, cartridge) witha gradient of EtOAc in hexanes (0-40%) to afford2-[3-Fluoro-2-(triisopropylsilyloxymethyl) phenyl] ethanol as an oil(2.44 g, 61% over 2 steps). ¹H NMR CDCl₃ 500 MHz, δ 7.30-7.24 (m, 1H),7.08 (d, J=7.6 Hz, 1H), 6.96 (ddd, J=9.5, 8.3, 1.1 Hz, 1H), 4.89 (d,J=2.1 Hz, 2H), 3.92 (t, J=6.2 Hz, 2H), 3.06 (t, J=6.2 Hz, 2H), 1.27-1.18(m, 3H), 1.12 (dd, J=7.1, 1.9 Hz, 18H).

Step 7:[2-[2-[(5-Bromo-6-chloro-2-nitro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methoxy-triisopropyl-silane

DIAD (1.00 mL, 5.08 mmol) was added drop wise to a solution of2-[3-fluoro-2-(triisopropylsilyloxymethyl) phenyl] ethanol (1.20 g, 3.68mmol), 5-bromo-6-chloro-2-nitro-pyridin-3-ol (1.02 g, 4.04 mmol), andtriphenylphosphine (1.45 g, 5.51 mmol) in toluene (39.0 mL) at roomtemperature. The mixture was stirred at room temperature for 48 h. Themixture was concentrated under reduced pressure, and the residue waspurified twice by silica gel chromatography with a gradient of MeOH inDCM (0-5%, 80 g, cartridge) and a gradient of ether in hexanes (0-10%,40 g, cartridge) to afford [2-[2-[(5-Bromo-6-chloro-2-nitro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methoxy-triisopropyl-silane as an oil (480mg, 23%). ¹H NMR CDCl₃ 500 MHz, δ 7.64 (s, 1H), 7.25-7.19 (m, 1H), 7.06(d, J=7.4 Hz, 1H), 6.96 (t, J=9.0 Hz, 1H), 4.88 (d, J=2.0 Hz, 2H), 4.42(t, J=6.6 Hz, 2H), 3.31 (t, J=6.6 Hz, 2H), 1.20-1.12 (m, 3H), 1.09-1.04(m, 18H).

Step 8: 5-Bromo-6-chloro-3-[2-[2-fluoro-6-(triisopropylsilyloxymethyl)phenyl]ethoxy]pyridin-2-amine

Fe (1.00 g, 17.9 mmol) was added to a solution of[2-[2-[(5-bromo-6-chloro-2-nitro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methoxy-triisopropyl-silane(1.09 g, 1.94 mmol) in HO Ac (18.0 mL) at 0° C. The mixture was slowlywarmed to room temperature and stirred for 2 h. The mixture was filteredthrough a pad of Celite. The Celite was washed with EtOAc (3×100 mL),and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (12 g, cartridge) with agradient of EtOAc in Hexanes (0-100%) to afford5-Bromo-6-chloro-3-[2-[2-fluoro-6-(triisopropylsilyloxymethyl)phenyl]ethoxy]pyridin-2-amine as an oil (978 mg, 95%). ¹H NMR CDCl₃ 500MHz, δ 7.26-7.20 (m, 1H), 7.04 (d, J=7.2 Hz, 1H), 7.02 (s, 1H), 6.96(ddd, J=9.5, 8.3, 1.0 Hz, 1H), 4.88 (d, J=2.0 Hz, 2H), 4.72 (s, 2H),4.25 (t, J=7.0 Hz, 2H), 3.30 (t, J=7.0 Hz, 2H), 1.19-1.11 (m, 3H),1.09-0.97 (m, 18H). m/z (ES+) [M-OTIPS]⁺: 359.05; HPLC t_(R)(A05)=3.07min.

Step 9:[2-[2-[(2-amino-5-bromo-6-chloro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methanol

TBAF (1.04 mL, 1.04 mmol) was added to a stirred solution of5-bromo-6-chloro-3-[2-[2-fluoro-6-(triisopropylsilyloxymethyl)phenyl]ethoxy]pyridin-2-amine (0.158 g, 0.297 mmol) in THF (2.00 mL) atroom temperature. The mixture was stirred at room temperature for 2 hand concentrated under reduced pressure. The residue was purified bysilica gel chromatography (12 g, cartridge) with MeOH in DCM (0-20%) toafford[2-[2-[(2-amino-5-bromo-6-chloro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methanol (0.105 mg, 94%) as a solid. ¹H NMR CD₃OD 400 MHz, δ 7.31-7.24(m, 1H), 7.23 (s, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.99 (ddd, J=9.6, 8.2,1.1 Hz, 1H), 4.76 (d, J=2.0 Hz, 2H), 4.27 (t, J=6.7 Hz, 2H), 3.30-3.26(m, 2H). m/z (ES+) [M+H]⁺: 377.0; HPLC t_(R) (A05)=2.46 min.

Step 10:5-Bromo-6-chloro-3-[2-[2-(chloromethyl)-6-fluoro-phenyl]ethoxy]pyridin-2-amine;hydrochloride

SOCl₂ (0.250 mL, 3.43 mmol) was added to a stirred solution of[2-[2-[(2-amino-5-bromo-6-chloro-3-pyridyl)oxy]ethyl]-3-fluoro-phenyl]methanol (0.670 g, 1.78 mmol) in THF (15.0 mL) at room temperature. Themixture was stirred at room temperature for 4 h. The mixture wasconcentrated under reduced pressure, and the residue was used as such inthe next step without further purification (636 mg, 83%). ¹H NMR CD₃OD400 MHz, δ 7.34-7.28 (m, 2H), 7.18 (d, J=7.6 Hz, 1H), 7.01 (ddd, J=9.5,8.4, 1.0 Hz, 1H), 4.79 (d, J=1.6 Hz, 1H), 4.31 (t, J=6.8 Hz, 1H),3.29-3.27 (m, 2H). m/z (ES+) [M+H]⁺: 395.09; HPLC t_(R) (A05)=2.66 min.

Step 11:3-Bromo-2-chloro-H-fluoro-6,7,12,13-tetrakydropyrido[2,3-c][5,2]benzoxazonine

Cs₂CO₃ (1.59 g, 0.153 mmol) and TBAI (0.636 g, 1.72 mmol) were added toa solution of5-bromo-6-chloro-3-[2-[2-(chloromethyl)-6-fluoro-phenyl]ethoxy]pyridin-2-amine(636 mg, 1.61 mmol) in DMF (400 mL) at room temperature under nitrogen.The mixture was heated to 70° C. for 5 h. The mixture was concentratedunder reduced pressure, and the residue was purified by silica gelchromatography (12 g, cartridge) with MeOH in DCM (0-20%) to afford3-bromo-2-chloro-11-fluoro-6,7,12,13-tetrahydropyrido[2,3-c][5,2]benzoxazonineas a solid (307 mg, 53%). ¹H NMR CDCl₃ 500 MHz, δ 7.59 (s, 1H), 7.19(td, J=8.0, 5.9 Hz, 1H), 7.10-6.95 (m, 3H), 4.58 (s, 2H), 4.33 (s, 2H),3.01 (s, 2H). m/z (ES+) [M+H]⁺: 359.0; HPLC t_(R)(B05)=2.61 min.

Step 12: Tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-13-carboxylate

Boc₂O (3.85 mL, 16.8 mmol) was added to a mixture of tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-13-carboxylate(300 mg, 0.839 mmol), Et₃N (2.92 mL, 21.0 mol), and DMAP (0.0102 g,0.0839 mmol) in THF (20.0 mL), and the mixture was stirred at roomtemperature for 12 h. DMAP (200 mg, 1.64 mmol) was added, and themixture was stirred for 72 h. The mixture was concentrated under reducedpressure, and the residue was purified by silica gel chromatography (40g, cartridge) with EtOAc and hexane (0-100%) to afford tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-13-carboxylateas a solid (293 mg, 76%). ¹H NMR CDCl₃ 500 MHz, δ 7.49 (s, 1H), 7.13(td, J=7.9, 5.6 Hz, 1H), 6.91-6.78 (m, 2H), 4.99 (s, 2H), 4.37 (s, 2H),2.92 (s, 2H), 1.40 (s, 9H). m/z (ES+) [M-tBu]⁺: 403.02; HPLC t_(R)(A05)=2.70 min.

Step 13: Tert-butyl 3-bromo-H-fluoro-2-hydrazino-7,12-dihydro-6Hpyrido[2,3-c][5,2]benzoxazonine-13-carboxylate

Hydrazine monohydrate (0.776 mL, 0.0160 mmol) was added to a solution oftert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-13-carboxylate(293 mg, 0.64 mmol) in EtOH (15.0 mL). The mixture was stirred at 105°C. for 36 h. The mixture was concentrated under reduced pressure, andthe residue was purified by silica gel chromatography (24 g, cartridge)with MeOH in DCM (0-15%) to afford tert-butyl3-bromo-11-fluoro-2-hydrazino-7,12-dihydro-6Hpyrido[2,3-c][5,2]benzoxazonine-13-carboxylate as a solid (232 mg, 80%).m/z (ES+) [M+2H-^(t)Bu]⁺: 399.02; HPLC t_(R) (A05)=2.39 min.

Step 14: tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate

TFA (1.90 μL, 0.0256 mmol) was added to a solution of tert-butyl3-bromo-11-fluoro-2-hydrazino-7,12-dihydro-6H-pyrido[2,3-c][5,2]benzoxazonine-13-carboxylate(232 mg, 0.512 mmol) in triethyl orthoformate (15.0 mL, 90.2 mmol). Themixture was heated to 100° C. for 1 h. The mixture was concentratedunder reduced pressure, and the residue was purified by silica gelchromatography (24 g, cartridge) with MeOH in DCM (0-30%) to affordtert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylateas a solid (218 mg, 92%). ¹H NMR (500 MHz, CDCl₃) δ 8.72 (s, 1H), 7.27(s, 1H), 7.10 (dd, J=13.9, 7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.68 (t,J=8.7 Hz, 1H), 4.91 (d, J=11.6 Hz, 1H), 4.72 (dt, J=11.8, 3.2 Hz, 1H),4.08 (t, J=11.6 Hz, 1H), 3.47 (t, J=13.2 Hz, 1H), 2.75 (d, J=14.7 Hz,1H), 1.69 (s, 1H), 1.46-1.30 (m, 9H). m/z (ES+) [M-^(t)Bu+2H]⁺: 409.01;HPLC t_(R) (A05)=2.37 min.

Step 15: tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate

Dioxane (1.70 mL) and water (0.300 mL) were sequentially added to amixture of tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(50.0 mg, 0.108 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (28.4mg, 0.130 mmol), Pd(dppf)Cl₂ (13.0 mg, 0.0178 mmol), and NaHCO₃ (50.0mg, 0.595 mmol) under N₂. The mixture was heated to 90° C. for 3 h. Themixture was diluted with DCM (10 mL) and filtered though Celite. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (12 g, cartridge) eluting withMeOH in DCM (0-30%) to afford tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylateas a solid (51.3 mg, >99%). m/z (ES+) [M-^(t)Bu+2H]⁺:420.14, HPLC t_(R)(A05)=2.29 min.

Step 16:12-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazoninehydrochloride

A solution of tert-butyl tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(25.8 mg, 0.0543 mmol) in HFIP (2.50 mL) was heated at 100° C. in an oilbath for 6 h. The mixture was concentrated under reduced pressure, andthe residue was purified by preparative HPLC (Gemini C18 30×100 mmAmBicarb/ACN 30-50%) to afford the free form of12-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazoninehydrochloride as a solid (16.2 mg, 80%). ¹H NMR (500 MHz, MeOD) δ 9.31(s, 1H), 8.44 (dd, J=5.0, 1.7 Hz, 1H), 7.73 (dd, J=7.7, 1.7 Hz, 1H),7.33 (dd, J=7.9, 4.8 Hz, 1H), 7.29 (s, 1H), 7.17 (td, J=7.9, 5.9 Hz,1H), 7.00 (d, J=7.7 Hz, 1H), 6.95-6.90 (m, 1H), 5.01 (s, 2H), 4.41 (s,2H), 3.13 (s, 2H), 2.32 (s, 3H). m/z (ES+)[M+H]⁺: 376.1, HPLC t_(R)(B05)=1.21 min.

HCl (0.0535 mmol, 13.4 μL, 4.0 M in 1,4-dioxane) was added drop wise toa solution of12-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine(16.2 mg, 0.0432 mmol) in DCM/MeOH (3.00 mL/0.300 mL). The mixture wasstirred at room temperature for 1 h. The mixture was concentrated underreduced pressure to afford12-fluoro-4-(2-methylpyridin-3-yl)-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazoninehydrochloride as a solid (23.3 mg, 74%). ¹H NMR MeOD 500 MHz, δ 9.34 (s,1H), 8.53 (dd, J=5.0, 1.2 Hz, 1H), 7.96 (dd, J=7.8, 1.2 Hz, 1H), 7.51(dd, J=7.7, 5.3 Hz, 1H), 7.39 (s, 1H), 7.18 (td, J=7.9, 5.9 Hz, 1H),7.01 (d, J=7.7 Hz, 1H), 6.98-6.90 (m, 1H), 5.03 (s, 2H), 4.42 (s, 2H),3.14 (s, 2H), 2.40 (s, 3H). ES+[M+H]⁺: 376.1, HPLC t_(R) (B05)=1.21 min.

Example 23:1-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-onebismesylate Step 1: tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate

1,4-Dioxane (1.80 mL) and water (0.350 mL) were sequentially added to amixture of tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(from Example 22; 50.0 mg, 0.108 mmol),l-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone (28.4 mg, 0.113 mmol), Pd(dppf)Cl₂ (11.8 mg, 0.0162 mmol), andNaHCO₃ (30.0 mg, 0.357 mmol) under N₂. The mixture was stirred at 90° C.for 2.5 h. The mixture was filtered though a short silica pad, washingwith DCM (3×5 mL). The filtrate was concentrated under reduced pressure,and the residue was purified by silica gel chromatography (12.0 gcartridge) eluting with MeOH in DCM (0-30%) to provide tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylateas a solid (66.1 mg, 97%, 80% purity), m/z (ES+) [M-tBu+2H]⁺: 552.2;HPLC t_(R) (B05)=2.28 min.

Step 2: tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate

A solution of tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(54.8 mg, 0.108 mmol) in MeOH (2.00 mL) was added to a flask chargedwith Pd/C (100 mg, 0.094 mmol) under nitrogen atmosphere at roomtemperature. The flask was evacuated and purged with H₂ 3 times. Themixture was stirred at 23° C. for 62 h and filtered through Celite,washing with MeOH (3×10.0 mL). The filtrated was concentrated underreduced pressure to provide tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylateas a solid (25.8 mg, 47%), which was used as such in the next stepwithout further purification, m/z (ES+) [M+H]⁺: 510.3; HPLC t_(R)(A05)=2.26 min.

Step 3:1-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one

A solution of tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(25.8 mg, 0.0506 mmol) in HFIP (2.50 mL) was heated at 100° C. for 3 h.The mixture was concentrated under reduced pressure, and the residue waspurified by preparative HPLC (BEH C18 30×150 mm AmBicarb/ACN 25-45%) to1-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneas a solid (11.1 mg, 53%). ¹H NMR MeOD 500 MHz, δ 9.23 (s, 1H), 7.13(td, J=8.0, 5.9 Hz, 1H), 7.10 (s, 1H), 6.96 (d, J=7.2 Hz, 1H), 6.87(ddd, J=9.9, 8.2, 0.9 Hz, 1H), 4.91 (s, 2H), 4.67 (ddt, J=13.2, 4.4, 2.2Hz, 1H), 4.42-4.29 (m, 2H), 4.02 (ddt, J=13.5, 4.1, 1.9 Hz, 1H),3.30-3.22 (m, 2H), 3.08 (s, 2H), 2.75 (td, J=13.0, 2.7 Hz, 1H), 2.13 (s,3H), 2.05-1.98 (m, 1H), 1.97-1.91 (m, 1H), 1.75-1.57 (m, 2H). m/z (ES+)[M+H]⁺:410.2; HPLC t_(R) (B05)=1.12 min.

Step 5:1-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-onebismesylate

MsOH (3.52 μL, 0.0542 mmol) was added to a solution of1-(4-(12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one(11.1 mg, 0.0271 mmol) in MeCN (1.50 mL) and water (0.500 mL) at rt. Themixture was stirred for 14 h and concentrated under reduced pressure toprovide the title compound as a solid (13.5 mg, 83%). ¹H NMR MeOD 500MHz, δ 9.42 (s, 1H), 7.77 (s, 1H), 7.19 (td, 7=7.9, 5.9 Hz, 1H), 7.01(d, J=7.6 Hz, 1H), 6.97-6.92 (m, 1H), 5.04 (s, 2H), 4.71 (ddt, 7=8.1,4.2, 2.1 Hz, 1H), 4.45 (s, 2H), 4.12-4.04 (m, 1H), 3.25 (td, 7=13.4, 2.8Hz, 1H), 3.19-3.05 (m, 3H), 2.76-2.71 (m, 1H), 2.71 (s, 6H), 2.14 (s,3H), 1.97-1.86 (m, 2H), 1.76 (ddd, 7=25.1, 12.6, 4.0 Hz, 1H), 1.63 (qd,7=12.4, 4.0 Hz, 1H). m/z (ES+) [M+H]⁺: 410.2; HPLC t_(R) (B05)=1.13 min.

Example 24:12-fluoro-4-(2-methylpyridin-3-yl)-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazoninehydrochloride salt Step 1: 5-bromo-6-chloro-3-iodo-pyridin-2-amine

Acetic acid (100 mL) was added to a mixture of5-bromo-6-chloro-pyridin-2-amine (10.4 g, 50.0 mmol) andA-iodosuccinimidc (12.4 g, 55.0 mmol). TFA (1.00 mL) was added, and themixture was stirred at 23° C. for 3 h. The mixture was poured intocrushed ice, and the aq. phase was diluted to pH 10 with ammoniumhydroxide (150 mL). The solid was filtered, washed with water andhexane, and dried under high vacuum to provide5-bromo-6-chloro-3-iodo-pyridin-2-amine as a solid (16.4 g, 98%). ¹H NMRCDCl₃ 400 MHz, δ 7.99 (d, J=0.8 Hz, 1H), 5.06 (br, 2H). m/z (ES+),[M+H]⁺: 332.9. HPLC (A05) t_(R)=2.46 min.

Step 2: 5-bromo-6-chloro-3-vinyl-pyridin-2-amine

DME (60.0 mL) and water (20.0 mL) were added to a mixture of5-bromo-6-chloro-3-iodo-pyridin-2-amine (6.67 g, 20.0 mmol), potassiumvinyltrifluoroborate (2.68 g, 20.0 mmol), K₂CO₃ (2.76 g, 20.0 mmol), andPd(dppf)Cl₂-DCM (1.63 g, 2.00 mmol). The mixture was heated to 85° C.for 18 h. After cooling down to 23° C., EtOAc (100 mL) was added, andthe mixture was filtered through Celite. The filtrate was washed withbrine (100 mL), and the organic phase was dried (MgSO₄), filtered, andconcentrated under reduced pressure. The product was purified by silicagel chromatography (80 g cartridge) eluting with hexanes and EtOAc(0-20%), followed by trituration from hexanes (50.0 mL) to provide5-bromo-6-chloro-3-vinyl-pyridin-2-amine as a solid (2.51 g; 54%). ¹HNMR CDCl₃500 MHz, δ 7.68 (s, 1H), 6.52 (ddd, J=17.3, 11.1, 0.6 Hz, 1H),5.70 (dd, J=17.4, 0.8 Hz, 1H), 5.48 (dd, J=11.1, 0.8 Hz, 1H), 4.70 (br,2H). m/z (ES+), [M+H]⁺: 232.9. HPLC (A05) t_(R)=2.38 min.

Step 3:5-bromo-6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-3-vinyl-pyridin-2-amine

5-bromo-6-chloro-3-vinyl-pyridin-2-amine (0.500 g, 2.14 mmol) wasdissolved in DMF (10.0 mL), and the mixture was cooled to 0° C. 60 wt. %NaH in mineral oil (0.343 g, 8.57 mmol) was added portion-wise, and themixture was stirred at 0° C. for 10 min. 4-Methoxybenzyl chloride (0.639mL, 4.71 mmol) was added, and the mixture was stirred at 0° C. for 1 h.Water (10.0 mL) was added drop-wise, and the mixture was stirred at 0°C. for 5 min. The aqueous phase was extracted with EtOAc (3×20.0 mL).The combined organic phases were washed with brine (20.0 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The productwas purified by silica gel chromatography (40 g cartridge) eluting withhexanes and EtOAc (0-10%) to provide5-bromo-6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-3-vinyl-pyridin-2-amineas an oil (0.859 g; 85%). ¹H NMR CDCl₃ 400 MHz, δ 7.78 (s, 1H),7.16-7.08 (m, 4H), 6.87-6.81 (m, 4H), 6.77 (dd, J=17.5, 10.9 Hz, 1H),5.64 (dd, J=17.5, 0.8 Hz, 1H), 5.35-5.28 (m, 1H), 4.35 (s, 4H), 3.80 (s,6H). m/z (ES+), [M+H]⁺: 473.1. HPLC (A05) t_(R)=2.98 min.

Step 4:2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-pyridine-3-carbaldehyde

1,4-Dioxane (21.0 mL) and water (7.00 mL) were added to5-bromo-6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-3-vinyl-pyridin-2-amine(0.845 g, 1.78 mmol). After cooling down to 0° C., 2,6-lutidine (0.415mL, 3.57 mmol), 4 wt. % OsO₄ in water (0.568 mL, 0.0892 mmol) and NaIO₄(0.763 g, 3.57 mmol) were added. The mixture was warmed to 23° C. andstirred for 18 h. Water (20.0 mL) was added, and the aqueous phase wasextracted with EtOAc (3×25.0 mL). The combined organic phases werewashed with brine (25.0 mL), dried (MgSO₄), filtered, and concentratedunder reduced pressure. The product was purified by silica gelchromatography (40 g cartridge) eluting with hexanes and EtOAc (0-15%)to provide2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-pyridine-3-carbaldehydeas an oil (0.675 g; 80%). ¹H NMR CDCl₃ 500 MHz, δ 9.80 (s, 1H), 8.09 (s,1H), 7.13-7.06 (m, 4H), 6.89-6.79 (m, 4H), 4.62 (s, 4H), 3.80 (s, 6H).m/z (ES+), [M+H]⁺: 475.1. HPLC (A05) t_(R)=2.84 min.

Step 5:[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methanol

2-[Bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-pyridine-3-carbaldehyde(0.670 g, 1.41 mmol) was dissolved in a mixture of THF (8.00 mL) andMeOH (2.00 mL). NaBH₄ (6.51 mg, 0.172 mmol) was added portion-wise, andthe mixture was stirred at 23° C. for 30 min. Sat. NH₄Cl (20.0 mL) wasadded drop-wise, and the aqueous phase was extracted with EtOAc (3×25.0mL). The combined organic phases were washed with brine (25.0 mL), dried(MgSO₄), filtered and concentrated under reduced pressure. The productwas purified by silica gel chromatography (25 g cartridge) eluting withhexanes and EtOAc (0-40%) to provide[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl] as anoil (0.558 g; 83%). ¹H NMR CDCl₃ 500 MHz, δ 7.80 (s, 1H), 7.18-7.11 (m,4H), 6.85-6.79 (m, 4H), 4.57 (d, J=5.4 Hz, 2H), 4.26 (s, 4H), 3.79 (s,6H), 2.50 (t, J=5.6 Hz, 1H). m/z (ES+), [M+H]⁺: 477.3. HPLC (A05)t_(R)=2.72 min.

Step 6: methyl 2-(bromomethyl)-6-fluoro-benzoate

Benzoyl peroxide (75.0%, 1.15 g, 3.57 mmol) was added to a solution ofmethyl 2-fluoro-6-methyl-benzoate (6.00 g, 35.7 mmol) and NBS (6.99 g,39.2 mmol) in CCl₄ (200 mL). The mixture was degassed by bubblingnitrogen through the solvent for 15 min. The mixture was heated to 80°C. for 12 h. Brine (100 mL) was added, and the aq. phase was extractedwith DCM (3×150 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (120 g cartridge) eluting withhexanes and EtOAc (0-10%) to provide methyl2-(bromomethyl)-6-fluoro-benzoate as an oil (5.70 g, 65%). ¹H NMR CDCl₃500 MHz, δ 7.44-7.33 (m, 1H), 7.22 (dd, J=7.7, 0.4 Hz, 1H), 7.08 (ddd,J=9.5, 8.4, 1.0 Hz, 1H), 4.65 (s, 2H), 3.98 (s, 3H). m/z (ES+), Noionization. HPLC (A05) t_(R)=2.40 min.

Step 7: methyl2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-benzoate

[2-[Bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methanol(2.00 g, 4.19 mmol) was dissolved in THF (20.0 mL), and the mixture wascooled to 0° C. 60 wt. % NaH in mineral oil (335 mg, 8.37 mmol) wasadded portion-wise, and the mixture was warmed to 23° C. After stirringfor 10 min, a solution of methyl 2-(bromomethyl)-6-fluoro-benzoate (1.55g, 6.28 mmol) in THF (10.0 mL) was added drop-wise. The mixture wasrefluxed for 12 h. After cooling to 0° C., sat. NH₄Cl (10.0 mL) wasadded drop-wise, and the mixture was stirred at 0° C. for 5 min. Theaqueous phase was extracted with EtOAc (2×100 mL), and the combinedorganic phases were washed with brine (50.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (80 g cartridge) eluting withhexanes and EtOAc (0-25%) to provide methyl2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-benzoateas an oil (2.10 g; 78%). ¹H NMR CDCl₃ 400 MHz, δ 7.79 (s, 1H), 7.41-7.31(m, 1H), 7.21-7.00 (m, 6H), 6.89-6.74 (m, 4H), 4.60 (s, 2H), 4.39 (s,2H), 4.30 (s, 4H), 3.82 (s, 3H), 3.79 (s, 6H). m/z (ES+), [M+H]⁺: 643.1.HPLC (A05) t_(R)=2.96 min.

Step 8:[2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-phenyl] methanol

Methyl2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-benzoate (2.10 g, 3.26 mmol) was dissolved in THF (30.0mL), and the mixture was cooled to −78° C. 1.0 M DIBAL-H in PhMe (13.0mL, 13.0 mmol) was added drop-wise. The mixture was warmed to 0° C. andstirred for 1 h. Rochelle's salt was added (50.0 mL). The mixture waswarmed to 23° C. and stirred until the solution became clear. The aq.phase was extracted with EtOAc (3×100 mL), and the combined organicphases were washed with brine (50.0 mL), dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (80 g cartridge) eluting with hexanes and EtOAc(0-40%) to provide[2-[[2-[bis[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-phenyl]methanolas an oil (1.90 g; 95%). ¹H NMR CDCl₃400 MHz, δ 7.78 (s, 1H), 7.28-7.21(m, 1H), 7.15-7.09 (m, 4H), 7.07 (t, 7=8.8 Hz, 1H), 6.99 (d, J=7.5 Hz,1H), 6.86-6.78 (m, 4H), 4.72 (dd, J=6.5, 1.5 Hz, 2H), 4.55 (s, 2H), 4.45(s, 2H), 4.32 (s, 4H), 3.79 (s, 6H), 2.35 (t, J=6.5 Hz, 1H). m/z (ES+),[M+H]⁺: 617.0. HPLC (A05) t_(R)=2.84 min.

Step 9:[2-[(2-amino-5-bromo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl]methanol

[2-[[2-[B is[(4-methoxyphenyl)methyl]amino]-5-bromo-6-chloro-3-pyridyl]methoxymethyl]-6-fluoro-phenyl]methanol(1.87 g, 3.04 mmol) was dissolved in DCM (15.0 mL). TFA (4.00 mL, 53.8mmol) was added drop-wise, and the mixture was stirred at 23° C. for 3h. The mixture was concentrated under reduced pressure. 2.0 N NaOH (50.0ml) was added to the residue, and the aq. phase was extracted with EtOAc(3×100 mL). The combined organic phases were washed with brine (100 mL),dried (MgSO₄), filtered, and concentrated under reduced pressure. Theproduct was purified by silica gel chromatography (80 g cartridge)eluting with EtOAc and hexane (0-50%) to provide[2-[(2-amino-5-bromo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl]methanol as a solid (1.00 g; 87%). ¹H NMR CDCl₃ 400 MHz, δ 7.50 (s, 1H),7.34-7.27 (m, 1H), 7.15-7.07 (m, 2H), 5.09 (s, 2H), 4.78 (dd, J=6.4, 1.7Hz, 2H), 4.63 (s, 2H), 4.47 (s, 2H), 2.26 (t, J=6.5 Hz, 1H). m/z (ES+),[M+H]⁺: 377.0. HPLC (A05) t_(R)=2.39 min.

Step 10:3-bromo-2-chloro-H-fluoro-5,7,12,13-tetrahydrobenzo[g]pyrido[3,2-c][f5]oxazonine

[2-[(2-Amino-5-bromo-6-chloro-3-pyridyl)methoxymethyl]-6-fluoro-phenyl]methanol(984 mg, 2.62 mmol) was dissolved in THF (15.0 mL). SOCl₂ (1.60 mL, 21.9mmol) was added, and the mixture was heated to 50° C. for 40 min (gasevolution). The mixture was concentrated under reduced pressure, and theresidue was repeatedly diluted with DCM and concentrated to remove anytrace of SOCl₂. The intermediate (m/z (ES+), [M-Cl]⁺: 394.9. HPLC (A05)t_(R)=2.60 m) was dried under high vacuum for 30 m. DMF (15.0 mL) wasadded to the solid followed by TBAI (968 mg, 2.62 mmol) and Cs₂CO₃ (2.56g, 7.86 mmol). The mixture was stirred at 100° C. for 50 min. Themixture was concentrated under reduced pressure. Water (50.0 mL) wasadded, and the aq. phase was extracted with EtOAc (3×100 mL). Thecombined organic phases were washed with brine (50.0 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The product waspurified by silica gel chromatography (24 g cartridge) eluting withhexane and EtOAc (0-25%) to provide3-bromo-2-chloro-11-fluoro-5,7,12,13-tetrahydrobenzo[g]pyrido[3,2-c][1,5]oxazonineas a solid (753 mg; 64%). ¹H NMR CDCl₃ 500 MHz, δ 7.59 (s, 1H),7.30-7.24 (m, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 5.43(t, J=7.2 Hz, 1H), 4.97 (s, 2H), 4.69 (dd, J=7.5, 2.0 Hz, 2H), 4.35 (s,2H). m/z (ES+), [M+H]⁺: 357.0. HPLC (A05) t_(R)=2.63 min.

Step 11: tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylate

Di-tert-butyl dicarbonate (0.443 mL, 1.93 mmol) was added to a solutionof3-bromo-2-chloro-11-fluoro-5,7,12,13-tetrahydrobenzo[g]pyrido[3,2-c][1,5]oxazonine(115 mg, 0.322 mmol), NEt₃ (0.134 mL, 0.965 mmol), and DMAP (9.82 mg,0.0804 mmol) in THF (2.00 mL). The mixture was heated to 50° C. for 15h. Water (5.00 mL) was added, and the aq. phase was extracted with EtOAc(3×20.0 mL). The combined organic phases were washed with brine (20.0mL), dried (MgSO₄), filtered, and concentrated under reduced pressure.The product was purified by silica gel chromatography (4 g cartridge)eluting with hexane and EtOAc (0-45%) to provide tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylateas a solid (91.0 mg; 62%). Complex NMR (rotamers). m/z (ES+),[M+H-tBu]⁺: 402.9. HPLC (A05) t_(R)=2.71 min.

Step 12: tert-butyl3-bromo-H-fluoro-2-hydrazineyl-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylate

A solution of tert-butyl3-bromo-2-chloro-11-fluoro-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylate(91.0 mg, 0.199 mmol) and hydrazine monohydrate (0.500 mL, 10.3 mmol) inEtOH (2.00 mL) was heated at 100° C. for 18 h. After cooling to 23° C.,the mixture was concentrated under reduced pressure. The product waspurified by silica gel chromatography (4 g cartridge) eluting with DCMand MeOH (0-10%) to provide tert-butyl3-bromo-11-fluoro-2-hydrazineyl-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylate as a solid (82.0 mg; 91%). Complex NMR (rotamers). m/z(ES+), [M+H-tBu]⁺: 397.0. HPLC (A05) t_(R)=2.40 min.

Step 13: tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

TFA (0.01 mL) was added to a solution of tert-butyl3-bromo-11-fluoro-2-hydrazineyl-7,12-dihydrobenzo[g]pyrido[3,2-c][1,5]oxazonine-13(5H)-carboxylate(82.0 mg, 0.181 mmol) in triethyl orthoformate (5.42 mL, 32.6 mmol). Themixture was heated to 100° C. for 1.5 h. After cooling to 23° C., themixture was concentrated under reduced pressure. The product waspurified by silica gel chromatography (4 g cartridge) eluting with DCMand MeOH (0-10%) to provide tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (66.0 mg; 78%). Complex NMR (rotamers). m/z (ES+),[M+H-tBu]⁺: 465.0. HPLC (A05) t_(R)=2.32 min.

Step 14: tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

1,4-Dioxane (1.50 mL) and water (0.300 mL) were added to a mixture oftert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(66.0 mg, 0.142 mmol), Pd(dppf)Cl₂ (10.4 mg, 0.0142 mmol), and NaHCO₃(35.9 mg, 0.427 mmol) under nitrogen. The mixture was heated to 90° C.for 2 h. After cooling to 23° C., the mixture was filtered though asilica plug washing with EtOAc. The filtrate was concentrated underreduced pressure. The product was purified by silica gel chromatography(24 g cartridge) eluting with DCM and MeOH (0-10%) to provide tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (60.0 mg; 89%). Complex NMR (rotamers). m/z (ES+), [M+H]⁺:476.2. HPLC (A05) t_(R)=2.24 min.

Step 15: tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylatehydrochloride salt

A solution of tert-butyl12-fluoro-4-(2-methylpyridin-3-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(53.0 mg, 0.111 mmol) in HFIP (1.50 mL) was heated to 100° C. for 15 h.After cooling to 23° C., the mixture was concentrated under reducedpressure. The product was purified by silica gel chromatography (24 gcartridge) eluting with DCM and MeOH (0-15%) to provide the free base ofthe title compound as a solid (28.0 mg; 67%). ¹H NMR (500 MHz, MeOD) δ9.50 (s, 1H), 8.48 (dd, 7=5.0, 1.7 Hz, 1H), 7.76 (dd, 7=7.7, 1.7 Hz,1H), 7.36 (dd, 7=7.7, 5.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.16 (d, J=7.5 Hz,1H), 7.05 (t, 7=9.1 Hz, 1H), 4.90 (d, J=1.4 Hz, 2H), 4.84 (s, 2H), 4.63(s, 2H), 2.33 (s, 3H). The compound was converted to the hydrochloridesalt by adding 4.0 N HCl in dioxane (18.6 μL, 0.0746 mmol) to a solutionof5-fluoro-15-(2-methyl-3-pyridyl)-11-oxa-2,17,18,20-tetrazatetracyclo[11.7.0.04,9.016,20]icosa-1(13),4(9),5,7,14,16,18-heptaene(28.0 mg, 0.0746 mmol) in DCM (5.00 mL) and MeOH (0.500 mL). The mixturewas stirred at 23° C. for 1 h. The mixture was concentrated underreduced pressure to afford the title compound as a solid (25.0 mg, 81%).¹H NMR MeOD 500 MHz, δ 9.62 (s, 1H), 8.74 (d, J=5.7 Hz, 1H), 8.45 (d,J=7.8 Hz, 1H), 7.93-7.89 (m, 1H), 7.53 (s, 1H), 7.38-7.29 (m, 1H), 7.15(d, 7=7.5 Hz, 1H), 7.09 (t, 7=9.0 Hz, 1H), 4.98 (s, 2H), 4.94 (s, 2H),4.67 (s, 2H), 2.58 (s, 3H). m/z (ES+), [M+H]⁺: 376.5. HPLC (A05)t_(R)=2.03 min.

Example 25:1-(4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneStep 1: tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

1,4-Dioxane (4.00 mL) and water (0.800 mL) were added to a mixture oftert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(Example 24; 113 mg, 0.244 mmol),l-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(67.4 mg, 0.268 mmol, Pd(dppf)Cl₂ (17.8 mg, 0.0244 mmol), and NaHCO₃(61.5 mg, 0.732 mmol) under nitrogen. The mixture was heated at 90° C.for 2.5 h. The mixture was cooled to 23° C. and filtered though a silicaplug, washing with EtOAc and 10% MeOH in DCM. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel chromatography (12 g cartridge) eluting with DCM and MeOH(0-10%) to provide tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (141 mg; 80% pure, 91%). Complex NMR (rotamers). m/z (ES+),[M+H]⁺: 508.1. HPLC (A05) t_(R)=2.22 min.

Step 2: tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

A solution of tert-butyl4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(111 mg, 0.175 mmol) in MeOH (12.0 mL) was added at 23° C. to a flaskcharged with 10% Pd/C (74.0 mg, 0.0695 mmol) under nitrogen atmosphere.The flask was evacuated and purged with H₂ gas 3 times. The mixture wasstirred at 23° C. for 1 h and filtered through Celite washing with MeOH.The filtrate was concentrated under reduced pressure, and the productwas purified by silica gel chromatography (24 g) eluting with DCM andMeOH (0-10%) to provide tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (71.0 mg, 80%). Complex NMR (rotamers). m/z (ES+) [M+H]⁺:510.2. HPLC (A05) t_(R)=2.20 min.

Step 3:1-(4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][P5]oxazonin-4-yl)piperidin-1-yl)ethan-1-onemethanesulfonyl salt

A solution of tert-butyl4-(1-acetylpiperidin-4-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(85.0 mg, 0.167 mmol) in HFIP (4.00 mL) was heated at 100° C. for 12 h.After cooling down to 23° C., the mixture was concentrated under reducedpressure. The product was purified by silica gel chromatography (12 gcartridge) eluting with DCM and MeOH (0-10%) to provide the free base of1-(4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneas a solid (40.0 mg; 59%). ¹H NMR (500 MHz, MeOD) δ 9.44-9.33 (m, 1H),7.33-7.23 (m, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.03 (t, J=9.1Hz, 1H), 4.73 (s, 2H), 4.72-4.68 (m, 1H), 4.69 (s, 2H), 4.52 (s, 2H),4.06 (d, J=13.8 Hz, 1H), 3.39-3.33 (m, 1H), 3.30-3.24 (m, 1H), 2.79 (t,J=13.0 Hz, 1H), 2.14 (s, 3H), 2.07 (d, J=13.1 Hz, 1H), 2.00 (d, J=13.2Hz, 1H), 1.82-1.63 (m, 2H). The compound was converted to themethanesulfonyl salt by adding MeSO₃H (3.01 μL, 0.0464 mmol) to asolution of1-(4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidin-1-yl)ethan-1-one(19.0 mg, 0.0464 mmol) in MeCN (2.00 mL). The mixture was stirred at 23°C. for 1 h. The mixture was concentrated under reduced pressure toprovide the title compound as a solid (21.0 mg, 89%). ¹H NMR MeOD 500MHz, δ 9.75 (s, 1H), 7.85 (s, 1H), 7.37 (td, J=7.9, 5.7 Hz, 1H),7.19-7.02 (m, 2H), 4.94 (s, 4H), 4.74 (d, J=13.5 Hz, 1H), 4.62 (s, 2H),4.12 (d, J=13.9 Hz, 1H), 3.36-3.26 (m, 1H), 3.24-3.15 (m, 1H), 2.84-2.75(m, 1H), 2.70 (s, 3H), 2.17 (s, 3H), 2.06-1.93 (m, 2H), 1.83 (qd,J=12.6, 3.8 Hz, 1H), 1.69 (qd, J=12.8, 4.2 Hz, 1H). m/z (ES+), [M+H]⁺:410.1. HPLC (A05) t_(R)=2.04 min.

Example 26:12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonineStep 1(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)(1-methyl-1H-pyrazol-4-yl)methanol

^(i)PrMgCl.LiCl (0.540 mL, 0.703 mmol) was drop wise added to a solutionof tert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(Example 24; 93.0 mg, 0.201 mmol) in THF (3.00 mL) at −78° C. undernitrogen. The mixture was stirred at −78° C. for 10 min and warmed to 0°C. for 30 min. A solution of 1-methylpyrazole-4-carbaldehyde (88.4 mg,0.803 mmol) in THF (1.00 mL) was drop wise added at 0° C. The mixturewas stirred at 0° C. for 30 min and warmed to room temperature for 2 h.The mixture was diluted with NH₄Cl (5 mL) and water (8 mL). The aqueousphase was extracted with ethyl acetate (5×20 mL). The combined organiclayers were dried over MgSO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography (12 g cartridge) eluting withMeOH in DCM (0-15%) to provide(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)(1-methyl-1H-pyrazol-4-yl)methanol(31 mg, 31%) as a solid, m/z (ES+) [M+H]⁺: 495.1; HPLC t_(R) (A05)=2.13min.

Step 2:12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine

Triethylsilane (0.400 mL, 2.51 mmol) and TFA (0.186 mL, 2.51 mmol) wereadded to a solution of(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)(1-methyl-1H-pyrazol-4-yl)methanol(31.0 mg, 0.0627 mmol) in MeCN (2.50 mL). The mixture was stirred at 60°C. for 3 h and concentrated under reduced pressure. The residue waspurified by HPLC (Torus-2PIC 10×250 mm MeOH/CO₂ 5-55% of MeOH) to affordthe title compound as a solid (7.47 mg, 31%). ¹H NMR (500 MHz, MeOD) δ9.39 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.28 (td, J=7.9, 5.6 Hz, 1H),7.15 (d, J=7.3 Hz, 1H), 7.07 (s, 1H), 7.02 (t, J=8.6 Hz, 1H), 4.73 (d,J=1.6 Hz, 2H), 4.67 (s, 2H), 4.49 (s, 2H), 4.04 (s, 2H), 3.82 (s, 3H).m/z (ES+) [M+H]⁺: 379.1; HPLC t_(R) (A05)=2.05 min.

Example 27:(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2b]benzofuro[4,3-fg][1,4]oxazonine

To a mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(2.4 g, 4.88 mmol, 1.00 eq; as prepared in Example 17) in DCM (20 mL)was added TFA (9.24 g, 81.0 mmol, 6 mL, 16.6 eq) in one portion at 18°C. The mixture was stirred at 18° C. for 12 hrs. TLC (Petroleumether:Ethyl acetate=0:1, R_(f)=0.2) detected one major new spot withlarger polarity. The mixture was evaporated to obtain the product. Tothe residue was added EtOAc (20 mL), then basified to pH=8 by saturatedaqueous NaHCO₃. The precipitate was generated. The mixture was filteredand the filter cake was washed with 10 mL of EtOAc, dried in vacuum togive(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(1.78 g, 4.55 mmol, 93% yield) as a gray solid.

Step 2:(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Dioxane (181 mL) and water (39.0 mL) were sequentially added to amixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(2.59 g, 6.62 mmol, 1.00 eq),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.74g, 7.94 mmol, 1.2 eq), Pd(dppf)Cl₂ (484 mg, 662 umol, 0.100 eq) andNaHCO₃ (2.78 g, 33.1 mmol, 1.29 mL, 5.00 eq) at 20° C. under N₂. Themixture was heated to 90° C. for 2 hrs. LC-MS showed no(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas remained. Several new peaks were shown on LC-MS and the desired masswas detected. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was combined with other twobatches (from 1.82 of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineand 1.0 g of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine)and to the residue (18 g) was added MeOH (100 mL) and silica-thiol (700mg, modified silicon gel for eliminating Pd, irregular silica gel,100-200 mesh, chlorides (Cl), %≤0.004, Particle Size Distribution 45-75um) at 20° C. and stirred at 20° C. for 12 hrs. The suspension wasfiltered and the filter cake was washed with 200 mL of MeOH and 20 mL ofDMSO, the filtrate was concentrated under reduced pressure to removeMeOH and purified by prep-HPLC (HCl condition: column: Phenomenex lunac18 250 mm*100 mm*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %:1%-31%, 25 min). The fraction of prep-HPLC was concentrated underreduced pressure to remove MeCN at 30° C. and the residue waslyophilized.(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(4.1 g, 9.29 mmol, 99.7% purity, 100% ee, HCl) was obtained as yellowsolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.89 (s, 1H), 8.86-8.75 (m, 1H),8.64-8.57 (m, 1H), 8.54-8.49 (m, 1H), 7.98-7.89 (m, 1H), 7.82-7.75 (m,1H), 7.03-6.92 (m, 1H), 6.71 (dd, J=8.6, 3.7 Hz, 1H), 5.00-4.91 (m, 1H),4.84 (br dd, J=14.7, 5.6 Hz, 1H), 4.58-4.45 (m, 2H), 4.25-4.17 (m, 1H),4.11-4.00 (m, 1H), 3.95-3.83 (m, 1H), 2.64 (s, 3H). LCMS (ESI+): m/z404.1 (M+H).

Example 28:(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-oneStep 1: tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Dioxane (2.00 mL) and water (0.400 mL) were added to a mixture oftert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 0.122 mol, 60.0 mg),1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone(0.128 mmol, 32.1 mg), Pd(dppf)Cl₂ (0.0122 mmol, 8.94 mg), and NaHCO₃(0.366 mmol, 30.8 mg) under N₂. The mixture was stirred at 90° C. for2.5 h. The mixture was filtered though a short silica pad. The filtercake was washed with EtOAc (3×5 mL). The filtrate was concentrated underreduced pressure, and the residue was purified by silica gelchromatography (4 g cartridge) eluting with MeOH in DCM (0-10%) toafford tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (53.6 mg, 82%). ES+[M]⁺:535.63; LC-MS (B05); t_(R)=2.23 min.

Step 2: tert-butyl(S)-4-(1-acetylpiperidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A solution of tert-butyl(S)-4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(99.0 μmol, 53.0 mg) in MeOH (10.0 mL) was added to a flask charged withPd/C (19.8 μmol, 21.1 mg, 10.0%) under nitrogen atmosphere at roomtemperature. The flask was evacuated and purged with H₂ gas 3 times. Themixture was stirred at rt for 20 h and filtered through Celite. Thefilter cake was washed with MeOH (3×8 mL), and the filtrate wasconcentrated under reduced pressure. The residue (53 mg) was used assuch in the next step without further purification, m/z (ES+)[M]⁺:537.75. HPLC (B05) t_(R)=2.09 min.

Step 3:(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidin-1-yl)ethan-1-one

A solution of tert-butyl(S)-4-(1-acetylpiperidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(98.6 μmol, 53.0 mg) in HFIP (2.00 mL) was heated to 100° C. for 3 h.The mixture was concentrated under reduced pressure, and the residue waspurified by HPLC (BEH C18 30×150 mm AmBicarb/ACN 25-45%) to afford thetitle compound as a solid (22.7 mg, 53%). ¹H NMR DMSO 500 MHz, δ 9.33(s, 1H), 7.15 (t, J=6.4 Hz, 1H), 7.07 (s, 1H), 6.97-6.84 (m, 1H), 6.66(dd, J=8.6, 3.8 Hz, 1H), 4.82 (dd, J=14.9, 5.9 Hz, 1H), 4.68 (dd,J=14.9, 6.6 Hz, 1H), 4.51 (t, J=9.4 Hz, 2H), 4.48-4.38 (m, 1H), 4.20(dd, J=9.6, 3.3 Hz, 1H), 4.02-3.86 (m, 2H), 3.77 (td, J=11.6, 4.2 Hz,1H), 3.26-3.09 (m, 2H), 2.67-2.55 (m, 1H), 2.02 (d, J=3.9 Hz, 3H),1.98-1.83 (m, 2H), 1.80-1.67 (m, 1H), 1.67-1.53 (m, 1H). m/z (ES+)[M+H]⁺: 438.61, HPLC (B05) t_(R)=1.91 min.

Example 29:(S)-12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1 tert-butyl(7aS)-12-fluoro-4-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 0.122 mmol, 60.0 mg) in THF (2.00 mL) was cooled to −78° C.^(i)PrMgCl.LiCl 0.427 mmol, 0.329 mL) was added drop-wise. The mixturewas stirred at −78° C. for 10 min and warmed to 0° C. for 30 min. Asolution of 1-methylpyrazole-4-carbaldehyde (0.488 mmol, 53.8 mg) in THF(1.00 mL) was added drop-wise at 0° C. The mixture was stirred at 0° C.for 30 min and warmed to room temperature for 2 h. The mixture wasdiluted with NH₄Cl (5 mL) and water (8 mL). The aqueous phase wasextracted with ethyl acetate (5×15 mL), and the combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (4 gcartridge) eluting with MeOH in DCM (0-15%) to provide tert-butyl(7aS)-12-fluoro-4-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (10.5 mg, 17%). LC-MS m/z (ES+) [M+H]⁺:523.88; (A05)t_(R)=2.02 min.

Step 2:(S)-12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl12-fluoro-4-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(0.0201 mmol, 10.5 mg) in MeCN (1.50 mL) was added Et₃SiH (0.804 mmol,0.0597 mL) and TFA (0.804 mmol, 0.128 mL). The mixture was stirred at60° C. for 3 h. The mixture was concentrated under reduced pressure, andthe residue was purified by HPLC (BEH C18 30×150 mm AmBicarb/ACN 25-45%)to afford the title compound as a solid (5.2 mg, 64%). ¹H NMR MeOD 400MHz, δ 9.23 (s, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.06 (s, 1H), 6.82 (dd,J=10.3, 8.7 Hz, 1H), 6.58 (dd, J=8.7, 3.8 Hz, 1H), 4.95 (d, J=14.8 Hz,1H), 4.77 (d, J=14.7 Hz, 1H), 4.57-4.42 (m, 2H), 4.23 (dd, J=9.6, 3.0Hz, 1H), 4.04-3.99 (m, 2H), 3.98-3.89 (m, 1H), 3.81 (s, 3H), 3.80-3.72(m, 1H). m/z (ES+) [M+H]⁺:407.62, HPLC (B05) t_(R)=1.93 min.

Example 30:(S)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineand(S)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

nitrogen (C₂H₅)₃SiH (7.93 mmol, 1.27 mL) and TFA (7.93 mmol, 0.589 mL)were added to a solution of(S)-12-fluoro-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(Example 30; 0.198 mmol, 100 mg) in MeCN (2.00 mL). The mixture washeated to 60° C. for 3 h. The mixture was concentrated. The residue waspurified by HPLC (BEH 30×150 mm ACN/AmBicarb 30-35%) to afford(S)-4-((1-methyl-1H-pyrazol-4-yl)methyl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineas a solid (8.00 mg, 10%). ¹H NMR (500 MHz, MeOD) δ 9.18 (s, 1H), 7.46(s, 1H), 7.36 (s, 1H), 7.11-7.04 (m, 2H), 6.84 (d, J=7.6 Hz, 1H), 6.62(d, J=7.9 Hz, 1H), 4.89-4.84 (m, 1H), 4.75 (d, J=14.3 Hz, 1H), 4.49 (t,J=9.3 Hz, 1H), 4.41 (dd, J=10.5, 4.3 Hz, 1H), 4.17 (dd, J=9.6, 3.4 Hz,1H), 4.02 (d, J=3.0 Hz, 2H), 3.99-3.92 (m, 1H), 3.81 (s, 3H), 3.78 (dd,J=11.9, 10.8 Hz, 1H). m/z (ES+) [M+H]⁺: 389.95; HPLC t_(R) (B05)=2.26min.

From the preceding purification,(S)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas isolated as a solid (9.00 mg, 15%). ¹H NMR (500 MHz, MeOD) δ 9.17(d, J=0.8 Hz, 1H), 7.37 (d, J=9.5 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.02(dd, J=9.5, 0.9 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.63 (d, J=7.9 Hz, 1H),4.94-4.85 (m, 1H), 4.79 (s, 1H), 4.51 (t, J=9.4 Hz, 1H), 4.47 (dd,J=10.4, 4.4 Hz, 1H), 4.19 (dd, J=9.6, 3.5 Hz, 1H), 3.98 (ddd, J=13.1,8.6, 4.0 Hz, 1H), 3.88-3.81 (m, 1H).

Example 31:(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Dioxane (1.50 mL) and water (0.300 mL) were added to a mixture oftert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 0.122 mmol, 60.0 mg),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(0.147 mmol, 34.3 mg), Pd(dppf)Cl₂ (0.0122 mmol, 8.94 mg), and NaHCO3(0.366 mmol, 30.8 mg) under N₂. The mixture was stirred at 90° C. for 4h. The mixture was filtered though a silica pad, and the filter cake waswashed with EtOAc (3×5 mL). The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel chromatography (4 gcartridge) eluting with MeOH in DCM (0-15%) to afford tert-butyl(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (60 mg, 95%). ES+[M]+: 518.47; LC-MS (B05) t_(R)=2.10 min.

Step 3:(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl (15R)-21-fluoro-10-(2,4-dimethylpyrimidyl)-13,17-dioxa-3,5,7,8-tetrazapentacyclo[13.6.1.04,12.05,9.018,22]docosa-1(21),4(12),6,8,10,18(22),19-heptaene-3-carboxylate(0.116 mmol, 60.0 mg) in HFIP (1.50 mL) was heated to 100° C. for 4 h.The mixture was concentrated under reduced pressure, and the residue waspurified by preparative HPLC (BEH C18 30×150 mm AmForm/ACN 35-45%_13min) to afford(S)-4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineas a solid (11.2 mg, 23%). ¹H NMR DMSO 400 MHz, δ 9.44 (s, 1H), 8.62 (s,1H), 7.62 (t, J=6.3 Hz, 1H), 7.41 (s, 1H), 7.04-6.89 (m, 1H), 6.70 (dd,J=8.6, 3.8 Hz, 1H), 4.92 (dd, J=15.1, 5.7 Hz, 1H), 4.79 (dd, J=15.1, 6.7Hz, 1H), 4.54 (t, J=9.4 Hz, 1H), 4.50-4.42 (m, 1H), 4.21 (dd, J=9.6, 3.5Hz, 1H), 4.10-3.99 (m, 1H), 3.88 (t, J=11.4 Hz, 1H), 2.63 (s, 3H), 2.35(s, 3H). ES+[M+H]+: 419.88; LC-MS (A05) t_(R)=1.91 min.

Example 32:4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine,3MsOH Step 1: tert-butyl4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate

Dioxane (1.33 mL) and water (0.265 mL) were sequentially added to amixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 50.0 mg, 0.108 mmol),2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(35.4 mg, 0.151 mmol), Pd(dppf)Cl₂ (11.8 mg, 0.0162 mmol), and NaHCO₃(27.2 mg, 0.324 mmol) under N₂. The mixture was stirred at 90° C. for 3h. The mixture was filtered though a short silica pad, washing with DCM(3×5 mL). The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel chromatography (12 g, cartridge)eluting with MeOH in DCM (0-15%) to afford tert-butyl4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylateas a solid (60.0 mg, 75% purity, 85%), which was used as such in thenext step. ES+[M+H]⁺:491.21; HPLC t_(R)=2.25 min.

Step 2:4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine

A solution of tert-butyl4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine-14(7H)-carboxylate(45.0 mg, 0.0917 mmol) in HFIP (3.00 mL) was heated to 100° C. for 4 h.The mixture was concentrated under reduced pressure, and the residue waspurified by preparative HPLC (BEH C18 30×150 mm AmBicarb/ACN 25-45%) toafford4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonineas a solid (14.7 mg, 41%). ES+[M+H]⁺: 391.2; HPLC t_(R)=2.08 min.

Step 3:4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine,3MsOH

4-(2,4-dimethylpyrimidin-5-yl)-12-fluoro-7,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzo[f][1,4]oxazonine(14.7 mg, 0.0377 mmol) was dissolved in MeOH (4.00 mL). MsOH (7.34 uL,0.113 mmol) was added, and the mixture was stirred for 2 h at rt. Themixture was concentrated under reduced pressure to afford the titlecompound as a solid (20.6 mg, 81%). ¹H NMR MeOD 500 MHz, δ 9.54 (s, 1H),8.84 (s, 1H), 8.00 (s, 1H), 7.24 (td, J=8.0, 5.9 Hz, 1H), 7.06 (d, J=6.9Hz, 1H), 7.03-6.98 (m, 1H), 5.17 (s, 2H), 4.51 (s, 2H), 3.19 (s, 2H),2.87 (s, 3H), 2.70 (s, 9H), 2.51 (s, 3H). ES+[M+H]⁺: 391.1; HPLCt_(R)=1.15 min.

Example 33:(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninehydrochloride Step 1: tert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A flask was charged with tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 0.12 g, 244 umol, 1.00 eq), 4-methyl-1H-imidazole (30.1 mg,366 umol, 1.5 eq) and K₃PO₄ (104 mg, 488 umol, 2.00 eq) at 15° C. andpurged with N₂. Another flask was charged with Pd₂(dba)₃ (11.2 mg, 12.2umol, 0.05 eq) andditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl) phenyl]phosphane (11.7 mg, 24.4 umol, 0.100 eq), toluene (2 mL) and dioxane(0.4 mL) at 15° C., then purged with nitrogen and heated at 120° C. for0.05 hr. Then it was cooled to 15° C. The obtained mixture(per-catalyst) was added to the first mixture via syringe. The resultingmixture was stirred at 120° C. for 10 h. LC-MS showed tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and the desired mass was detected. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Ethyl acetate/Methanol=10/1) to affordtert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(40 mg) and(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(15 mg). They were confirmed by LCMS, respectively, tert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.04 g, 81.22 umol, 33% yield) was obtained as a brown solid and usedin the next step directly.(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas further purified by prep-HPLC (formic acid conditions) (column: LunaC18 100*30 5 u; mobile phase: [water (0.2% FA)-ACN]; B %: 10%-25%, 12min) to afford pure(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(3.20 mg, 7.15 umol, 2% yield, 97.974% purity, formate salt) as a yellowsolid, which was combined with the other batch (de-Boc of tert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate).

Step 2:(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninehydrochloride

To a solution of tert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.030 g, 60.9 umol, 1.00 eq) in DCM (1 mL) was added TFA (1.54 g, 13.5mmol, 1.00 mL, 222 eq) at 15° C. The mixture was stirred at 15° C. for 1hr. LC-MS showed tert-butyl(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was blown to dryness by nitrogen stream.The residue was purified by prep-HPLC (formic acid conditions) (column:Luna C18 100*30 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 1%-30%,12 min). The fraction was combined with batch((S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninefrom previous step, 3.2 mg as formate salt) and lyophilized together.Then one drop of 6 N of aqueous HCl solution was added and lyophilizedagain.(S)-12-fluoro-4-(4-methyl-1H-imidazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(11.5 mg, 26.5 umol, 98.8% purity, HCl) was obtained as a yellow solid.¹H NMR CD₃OD 400 MHz, 8=ppm 9.82 (s, 1H), 9.33 (s, 1H), 8.40 (s, 1H),7.71 (s, 1H), 6.93 (t, J=9.48 Hz, 1H), 6.69 (dd, J=8.68, 3.79 Hz, 1H),5.20 (br d, J=14.79 Hz, 1H), 5.02 (br d, J=14.18 Hz, 1H), 4.80 (br s,1H), 4.64 (t, 7=9.41 Hz, 1H), 4.34 (br dd, J=9.66, 2.81 Hz, 1H), 4.11(br s, 1H), 4.06-3.93 (m, 1H), 2.49 (s, 3H). LCMS (ESI+): m/z 393.2(M+H).

Example 34: methyl(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylatemesylate salt Step 1: tert-butyl(S)-4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Dioxane (2.00 mL) and water (0.400 mL) were added to a mixture oftert-butyl(R)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 0.204 mmol, 100 mg), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(0.305 mmol, 94.4 mg), Pd(dppf)Cl₂ (0.0204 mmol, 14.9 mg), and NaHCO₃(0.611 mmol, 51.3 mg) under N₂. The mixture was stirred at 90° C. for 2h. The mixture was filtered though a silica pad. The filter cake waswashed with EtOAc (3×5 mL), and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(4 g cartridge) eluting with MeOH in DCM (0-10%) to afford tert-butyl(S)-4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(102 mg, 84%). ES+[M]⁺:593.48; LC-MS (A05); t_(R)=2.49 min.

Step 2: tert-butyl(S)-4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A solution of tert-butyl(S)-4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(172 μmol, 102 mg) in MeOH (10.0 mL) was added to a flask charged withPd/C (34.4 μmol, 36.6 mg, 10.0%) under a nitrogen atmosphere at roomtemperature. The flask was evacuated and purged with H₂ gas 3 times. Themixture was stirred at rt for 20 h. The mixture was filtered throughCelite, and the filter cake was washed with MeOH (3×8 mL). The filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel chromatography (4 g cartridge) eluting with MeOH in DCM(0-15%) to afford tert-butyl(S)-4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (81.2 mg, 79%). m/z (ES+) [M]⁺:596.32, LC-MS, (A05)t_(R)=2.52 min.

Step 3:(S)-12-fluoro-4-(piperidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

TFA (2.73 mmol, 0.209 mL) was added to a solution of tert-butyl(S)-4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(136 μmol, 81.2 mg) in DCM (2.00 mL) at room temperature. The mixturewas stirred at room temperature for 8.5 h. The mixture was concentratedunder reduced pressure and used as such in the next step without furtherpurification, m/z (ES+) [M]⁺: 395.54; LC-MS (A05), t_(R)=1.69 min.

Step 5: methyl(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylate

Methyl chloroformate (150 μmol, 14.2 mg, 11.6 μL) was added drop wise toa solution of(S)-12-fluoro-4-(piperidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(136 μmol, 53.9 mg) and triethylamine (818 μmol, 82.8 mg, 114 μL) in DCM(2.00 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixturewas concentrated under reduced pressure, and the residue was purified byHPLC (Gemini C18 30×100 mm AmBiCarb/ACN 36-56%) to afford methyl(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylateas a solid (30.5 mg, 49%). ¹H NMR DMSO 500 MHz, δ 9.32 (s, 1H), 7.14 (t,J=6.4 Hz, 1H), 7.07 (s, 1H), 6.92 (dd, J=10.2, 8.8 Hz, 1H), 6.66 (dd,J=8.6, 3.8 Hz, 1H), 4.82 (dd, J=14.9, 5.9 Hz, 1H), 4.68 (dd, J=15.0, 6.9Hz, 1H), 4.51 (t, J=9.4 Hz, 1H), 4.44 (d, J=6.4 Hz, 1H), 4.20 (dd,J=9.6, 3.3 Hz, 1H), 4.15-4.03 (m, 2H), 4.02-3.91 (m, 1H), 3.78 (t,J=11.5 Hz, 1H), 3.61 (s, 3H), 3.22-3.09 (m, 1H), 2.91 (brs, 2H), 1.89(t, J=13.7 Hz, 2H), 1.76-1.60 (m, 2H). m/z (ES+) [M]⁺:453.25; LC-MS(A05); t_(R)=2.17 min.

Step 6: methyl(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylatemesylate salt

MeSO₃H (0.0529 mmol, 3.44 μL) was added to a stirred suspension ofmethyl(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)piperidine-1-carboxylate(0.0529 mmol, 24.0 mg) in MeCN (1.00 mL) at room temperature. Themixture was stirred at room temperature for 1 h. The solution wasconcentrated under reduced pressure to afford the title compound as asolid (26.3 mg, 90%). ¹H NMR DMSO 500 MHz, δ 9.59 (s, 1H), 7.96 (s, 1H),7.68 (s, 1H), 6.96 (dd, J=10.2, 8.8 Hz, 1H), 6.70 (dd, J=8.6, 3.8 Hz,1H), 4.89 (dd, J=14.9, 5.3 Hz, 1H), 4.75 (dd, J=14.9, 6.8 Hz, 1H),4.61-4.56 (m, 1H), 4.54 (t, J=9.5 Hz, 1H), 4.23 (dd, J=9.7, 3.5 Hz, 1H),4.13 (s, 2H), 4.01 (ddd, J=13.6, 8.5, 3.9 Hz, 1H), 3.82 (t, J=11.4 Hz,1H), 3.61 (s, 3H), 3.08 (tt, J=12.0, 3.2 Hz, 1H), 2.89 (s, 2H), 2.32 (s,3H), 1.81 (t, J=13.4 Hz, 2H), 1.76-1.50 (m, 2H). m/z (ES+) [M-MsOH]⁺:453.52; LC-MS (A05) t_(R)=2.04 min.

Example 35:(S)-12-fluoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

To a solution of 5-bromo-4-methylpyrimidine (700 mg, 4.05 mmol, 1.00eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.34 g, 5.26 mmol, 1.3 eq) in dioxane (10 mL) was added KOAc (794 mg,8.09 mmol, 2.00 eq) Pd(dppf)Cl₂ (296 mg, 405 umol, 0.100 eq) at 25° C.,then the mixture was stirred at 80° C. under nitrogen for 12 h. LCMSshowed the reaction was complete, starting material was consumed,desired target MS was detected. The mixture was concentrated, thendissolved with EtOAc (15 mL), filtered, the filtrate was concentrated.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 0/1 and then Ethyl acetate/MeOH=1/0 to 0/1).4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(0.800 g, 3.64 mmol, 89% yield) was obtained as a yellow oil. ¹H NMRCDCl₃400 MHz, δ=ppm 9.08 (s, 1H), 8.90 (s, 1H), 2.71 (s, 3H), 1.36 (s,12H).

Step 2:(S)-12-fluoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (56.3mg, 256 umol, 2.00 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(50.0 mg, 128 umol, 1.00 eq) in dioxane (5 mL), water (0.5 mL) was addedNaHCO₃ (53.7 mg, 639. umol, 24.9 uL, 5.00 eq), Pd(dppf)Cl₂ (9.35 mg,12.8 umol, 0.100 eq) in 25° C., then the mixture was stirred at 80° C.for 6 h. LCMS showed the reaction was complete, starting material wasconsumed, desired target mass was detected. The mixture was concentratedunder reduced pressure, dissolved in Ethyl acetate (20 mL), thenfiltered, the filtrate was concentrated under reduced pressure to affordcrude product. The crude product was purified by prep-HPLC (column: LunaC18 100*30 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 20%-50%, 12min).(S)-12-fluoro-4-(4-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(19.8 mg, 48.2 umol, 37% yield, 98.5% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.46 (s, 1H), 9.06 (s, 1H), 8.76(s, 1H), 7.69-7.62 (m, 1H), 7.48 (s, 1H), 6.98 (br t, J=9.4 Hz, 1H),6.71 (br dd, J=8.4, 3.5 Hz, 1H), 4.98-4.89 (m, 1H), 4.86-4.74 (m, 1H),4.54 (br d, 7=9.5 Hz, 1H), 4.52-4.45 (m, 1H), 4.22 (br dd, 7=9.4, 3.4Hz, 1H), 4.05 (br d, 7=3.5 Hz, 1H), 3.95-3.83 (m, 1H), 2.41 (s, 3H).LCMS (ESI+): m/z 405.1 (M+H).

Example 36:(S)-12-fluoro-4-(2-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a stirred solution of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (45.0mg, 205 umol, 2.00 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(40.0 mg, 102 umol, 1.00 eq) and NaHCO₃ (43.0 mg, 511 umol, 19.9 uL,5.00 eq) in dioxane (3.00 mL) and water (0.60 mL) was added Pd(dppf)Cl₂(7.48 mg, 10.2 umol, 0.100 eq) at 15° C. under N₂. The resulting mixturewas stirred at 90° C. for 2 h. The mixture was concentrated underreduced pressure. The residue was purified by neutral prep-HPLC.(S)-12-fluoro-4-(2-methylpyrimidin-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(8.20 mg, 19.5 umol, 19% yield, 96.0% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.48 (s, 3H), 7.93 (s, 1H), 7.73(br s, 1H), 6.96 (t, 7=9.3 Hz, 1H), 6.69 (dd, 7=8.6, 3.9 Hz, 1H),4.97-4.87 (m, 1H), 4.83 (br s, 1H), 4.54 (br t, 7=9.2 Hz, 2H), 4.23 (dd,7=9.6, 3.2 Hz, 1H), 4.03 (br d, 7=9.0 Hz, 1H), 3.99-3.90 (m, 1H), 2.66(s, 3H). LCMS (ESI+): m/z 405.1 (M+H).

Example 37:(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole

The reaction was set up as two separate batches. To a solution of4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (450 mg, 2.38 mmol, 1.00 eq)in DCM (8 mL) was added DAST (2.30 g, 14.3 mmol, 1.89 mL, 6 eq) at 0°C., then the mixture was stirred at 20° C. for 5 h under nitrogenatmosphere. LCMS indicated that the complete conversion. The batcheswere combined, aq. NaHCO₃ (5%, 6 mL) was added dropwise to the reactionsolution under ice bath cooling to adjust pH to 7-8, then the mixturewas extracted with EtOAc (10 mL*3), the organic layers were dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to3/1; Petroleum ether/Ethyl acetate=3/1, R_(f)=0.4).4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (830 mg, 3.93 mmol, 82%yield) was obtained as a light brown oil.

Step 2: (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid

To a solution of 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (400mg, 1.90 mmol, 1.00 eq) in THF (10 mL) was added n-BuLi (2.5 M, 910 uL,1.2 eq) at −78° C., the mixture was stirred at −78° C. for 0.5 hr, thentriisopropyl borate (1.07 g, 5.69 mmol, 1.31 mL, 3.00 eq) was added tothe mixture at −78° C., the mixture was stirred at −78° C. for 1.5 h.LCMS showed 4-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole was consumedcompletely and the desired mass was detected. Water (10 mL) was added tothe mixture, then the mixture was concentrated. The residue was purifiedby prep-HPLC (column: Xbridge 150*30 mm*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 1%-20%, 10 min).(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid (110 mg, 625umol, 32% yield) was obtained as a white solid.

Step 3:(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(60.0 mg, 153.4 umol, 1.00 eq) in dioxane (1 mL), water (0.1 mL) wasadded (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid (67.5mg, 383 umol, 2.5 eq), Pd(dppf)Cl₂ (11.2 mg, 15.3 umol, 0.100 eq) andNaHCO₃ (64.4 mg, 767 umol, 29.8 uL, 5.00 eq) at 20° C., the mixture wasstirred at 80° C. for 12 h under N₂. LC-MS showed that(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas consumed completely and the desired mass was detected. The reactionwas filtered, the filtrate was concentrated. The residue was purified byprep-HPLC (column: Luna C18 100*30 5 u; mobile phase: [water (0.2%FA)-ACN]; B %: 35%-45%, 12 min).(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.0 mg, 56.0 umol, 36% yield, 99.1% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.43 (s, 1H), 8.61 (s, 1H), 7.47(br t, J=6.4 Hz, 1H), 7.41 (s, 1H), 7.24 (t, J=54.0 Hz, 1H), 6.99-6.91(m, 1H), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 4.93-4.73 (m, 2H), 4.57-4.42 (m,2H), 4.24 (dd, J=9.5, 3.3 Hz, 1H), 4.04 (br s, 1H), 3.96 (s, 3H),3.89-3.80 (m, 1H). ¹H NMR CDCl₃ 400 MHz, δ=ppm 8.77 (s, 1H), 8.73 (s,1H), 7.47 (br t, J=6.4 Hz, 1H), 7.41 (s, 1H), 6.92-6.82 (m, 1H), 6.85(t, J=54.0 Hz, 1H), 6.67 (dd, J=8.6, 3.9 Hz, 1H), 5.13-5.05 (m, 1H),4.88-4.80 (m, 1H), 4.70-4.60 (m, 2H), 4.30 (dd, J=9.5, 3.3 Hz, 1H), 3.99(s, 3H), 3.97-3.80 (m, 2H). LCMS (ESI+): m/z 443.1 (M+H).

Example 38:(S)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-oneand(R)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-oneStep 1:1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a solution of 4-bromo-1-methylpyridin-2(1H)-one (950 mg, 5.05 mmol,1.00 eq) in dioxane (50 mL) was added KOAc (1.49 g, 15.2 mmol, 3.00 eq),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.80 g,7.07 mmol, 1.4 eq) and Pd(dppf)Cl₂.DCM (413 mg, 505 umol, 0.100 eq). Themixture was stirred at 110° C. for 2 hrs under nitrogen atmosphere. LCMSshowed the starting material was consumed completely and the desired MSwas detected. The reaction mixture was concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Ethyl acetate:Methanol=0:1 to 1:0).1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(650 mg, crude) was obtained as yellow oil. ¹H NMR CDCl₃ 400 MHz, δ=ppm7.27-7.21 (m, 1H), 7.01 (s, 1H), 6.40 (d, J=6.6 Hz, 1H), 3.53 (s, 3H),1.31 (s, 12H).

Step 2:(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one

To a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(397 mg, 1.69 mmol, 2.2 eq) in dioxane (10 mL) and water (2 mL) wasadded NaHCO₃ (193 mg, 2.30 mmol, 89.5 uL, 3.00 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(Example 17; 300 mg, 767 umol, 1.00 eq) and Pd(dppf)Cl₂ (56.1 mg, 76.7umol, 0.100 eq) under nitrogen atmosphere. The mixture was stirred at80° C. for 8 hrs. LCMS showed the starting material was consumedcompletely and the desired MS was detected. The reaction mixture wasfiltered and the filter cake was washed by MeOH (20 mL). The filter cakewas dried under reduced pressure to give a crude product. The crudeproduct was used to the next step without further purification.(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one(280 mg, crude) was obtained as a green solid. ¹H NMR DMSO-d₆ 400 MHz,δ=ppm 9.39 (s, 1H), 7.80 (s, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.01 (s,1H), 6.92 (s, 1H), 6.65 (s, 1H), 4.89 (s, 2H), 4.51 (s, 2H), 4.04-3.90(m, 2H), 4.04-3.89 (m, 3H), 3.32 (s, 3H).

Step 3:(S)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-oneand(R)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one

To a solution of(S)-4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one(190 mg, 453 umol, 1.00 eq) in MeOH (20 mL) was added AcOH (10.5 g, 175mmol, 10.0 mL, 386 eq) and 10% Pd/C (200 mg, 50% purity at 20° C. Themixture was stirred at 50° C. for 5 hrs under H₂ (15 Psi) atmosphere.LCMS showed most of the starting material was consumed and the desiredMS was detected. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (formic acid conditions) to give4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one(120 mg). The diastereomers were separated by chiral SFC. Columnconditions: Waters Prep 80Q SFC; Chiralpak AD, 250*30 mm i.d. 10 u;Mobile phase A for CO₂; Mobile phase B for MeOH (0.1% NH₃H₂O)—CH₃CN(2:1); Gradient, B %=50%; Flow rate, 80 g/min; 40° C.; 100 bar.

(S)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one(54.4 mg, 126.6 umol, 27% yield, 98.6% purity) (Rt=1.71 min) wasobtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.35 (s, 1H),7.22 (t, J=6.2 Hz, 1H), 7.09 (s, 1H), 6.93 (t, J=9.5 Hz, 1H), 6.68 (dd,7=8.6, 3.7 Hz, 1H), 4.87-4.80 (m, 1H), 4.75-4.67 (m, 1H), 4.52 (t, 7=9.4Hz, 1H), 4.44 (d, J=6.4 Hz, 1H), 4.21 (dd, 7=9.6, 3.1 Hz, 1H), 4.04-3.95(m, 1H), 3.84-3.76 (m, 1H), 3.49-3.39 (m, 2H), 3.32-3.25 (m, 1H), 2.86(s, 3H), 2.60 (d, J=8.3 Hz, 2H), 2.16-2.06 (m, 2H). LCMS (ESI+): m/z424.2 (M+H).

(R)-4-((S)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpiperidin-2-one(41.6 mg, 93.64 umol, 20% yield, 95.254% purity) (Rt=2.44 min) wasobtained as a white solid. ¹H NMR ET15715-773-P2B2 DMSO-d₆ 400 MHz,δ=ppm 9.36 (s, 1H), 7.23 (t, 7=6.1 Hz, 1H), 7.08 (s, 1H), 6.93 (t, J=9.5Hz, 1H), 6.67 (dd, 7=8.6, 3.7 Hz, 1H), 4.84 (dd, 7=15.0, 5.7 Hz, 1H),4.73-4.65 (m, 1H), 4.52 (t, 7=9.4 Hz, 1H), 4.46 (d, J=5.6 Hz, 1H), 4.23(dd, 7=9.5, 2.8 Hz, 1H), 3.98 (br s, 1H), 3.85-3.77 (m, 1H), 3.43 (dd,J=10.4, 5.5 Hz, 2H), 3.32-3.28 (m, 1H), 2.86 (s, 3H), 2.60-2.56 (m, 2H),2.18-2.10 (m, 2H). LCMS (ESI+): m/z 424.2 (M+H).

Example 39: methyl4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidine-1-carboxylatemethanesulfonyl salt Step 1: tert-butyl12-fluoro-4-(1-(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

1,4-Dioxane (3.00 mL) and water (0.600 mL) were added to a mixture oftert-butyl4-bromo-12-fluoro-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(from Example 24; 99.0 mg, 0.214 mmol), methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(68.5 mg, 0.256 mmol), Pd(dppf)Cl₂ (15.6 mg, 0.0214 mmol), and NaHCO₃(53.9 mg, 0.641 mmol) under nitrogen. The mixture was heated to 90° C.for 2.5 h. After cooling to 23° C., the mixture was filtered though asilica plug which was then washed with EtOAc and 10% MeOH in DCM. Thecombined filtrates were concentrated under reduced pressure. The productwas purified by silica gel chromatography (12 g cartridge) eluting withDCM and MeOH (0-10%) to provide tert-butyl12-fluoro-4-(1-(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (107 mg, 77%). Complex NMR (rotamers). m/z (ES+), [M+H]⁺:524.2. HPLC (A05) t_(R)=2.37 min.

Step 2: tert-butyl12-fluoro-4-(1-(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate

A solution of tert-butyl12-fluoro-4-(1-(methoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(102 mg, 156 μmol) in MeOH (12.0 mL) was added at 23° C. to a flaskcharged with 10% Pd/C (65.9 mg, 0.0619 mmol) under nitrogen atmosphere.The flask was evacuated and purged with H₂ gas 3 times. The mixture wasstirred at 23° C. for 1.5 h and filtered through Celite washing withMeOH. The filtrate was concentrated under reduced pressure. The productwas purified by silica gel chromatography (12 g) eluting with DCM andMeOH (0-10%) to provide tert-butyl12-fluoro-4-(1-(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylateas a solid (69.0 mg, 84%). Complex NMR (rotamers). m/z (ES+) [M+H]+:526.2. HPLC (A05) t_(R)=2.33 min.

Step 3: methyl4-(12-fluoro-6,8,13,14-tetrahydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonin-4-yl)piperidine-1-carboxylatemesylate

A solution of tert-butyl12-fluoro-4-(1-(methoxycarbonyl)piperidin-4-yl)-8,13-dihydro-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-c]benzo[g][1,5]oxazonine-14(6H)-carboxylate(69.0 mg, 0.131 mmol) in HFIP (4.00 mL) was heated to 100° C. for 12 h.After cooling to 23° C., the mixture was concentrated under reducedpressure. The product was purified by silica gel chromatography (12 gcartridge) eluting with DCM and MeOH (0-10%) to provide the free base ofthe title compound as a solid (48.0 mg; 86%). ¹H NMR (500 MHz, MeOD) δ9.39 (s, 1H), 7.29 (td, J=7.9, 5.7 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.14(s, 1H), 7.03 (t, J=9.0 Hz, 1H), 4.73 (s, 2H), 4.68 (s, 2H), 4.52 (s,2H), 4.26 (d, J=10.7 Hz, 2H), 3.71 (s, 3H), 3.29-3.24 (m, 1H), 3.08-2.92(m, 2H), 1.99 (d, J=12.9 Hz, 2H), 1.70 (qd, J=12.6, 4.1 Hz, 2H). Thecompound was converted to the methanesulfonyl salt by addition of MeSO₃H(3.36 μL, 51.7 mmol) to a solution the free base (22.0 mg, 0.0517 mmol)in MeCN (2.00 mL). The mixture was stirred at 23° C. for 1 h. Themixture was concentrated under reduced pressure to provide the titlecompound as a solid (24.0 mg, 89%). ¹H NMR MeOD 500 MHz, δ 9.74 (s, 1H),7.85 (s, 1H), 7.37 (td, J=8.0, 5.7 Hz, 1H), 7.20-7.04 (m, 2H), 4.94 (s,2H), 4.93 (s, 2H), 4.61 (s, 2H), 4.31 (d, J=12.2 Hz, 2H), 3.72 (s, 3H),3.19-3.07 (m, 1H), 3.06-2.94 (m, 2H), 2.70 (s, 3H), 1.93 (d, J=13.1 Hz,2H), 1.74 (qd, J=12.4, 4.1 Hz, 2H). m/z (ES+), [M+H]⁺: 426.5. HPLC (A05)t_(R)=2.15 min.

Example 40:(S)-4-ethyl-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:(S)-12-fluoro-4-vinyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 255.63 umol, 1.00 eq),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (78.7 mg, 511 umol, 86.7uL, 2.00 eq) and NaHCO₃ (107 mg, 1.28 mmol, 49.7 uL, 5.00 eq) in dioxane(2 mL) and water (0.2 mL) was added Pd(dppf)Cl₂ (18.70 mg, 25.56 umol,0.100 eq) at 25° C. The resulting mixture was stirred at 80° C. undernitrogen for 2.5 h. The mixture was concentrated under reduced pressure.The residue was purified by prep-TLC (SiO₂, EtOAc:MeOH=20:1).(S)-12-fluoro-4-vinyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, crude) was obtained as yellow solid.

Step 2:(S)-4-ethyl-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-12-fluoro-4-vinyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(90.0 mg, 266 umol, 1.00 eq) in MeOH (4 mL) was added 10% Pd/C (90.0 mg,50% purity) at 25° C. The mixture was stirred at 40° C. under H₂ (15psi) for 1 hr. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by acidicprep-HPLC (column: Luna C18 100*30 5 u; mobile phase: [water (0.225%FA)-ACN]; B %: 10%-50%, 12 min).(S)-4-ethyl-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(11.7 mg, 32.9 umol, 12% yield, 95.6% purity) was obtained as a whitesolid. ¹H NMR CDCl₃ 400 MHz, δ=ppm 8.68 (s, 1H), 6.80 (s, 1H), 6.80-6.72(m, 1H), 6.56 (dd, J=8.6, 3.9 Hz, 1H), 4.92 (br dd, J=14.5, 7.4 Hz, 1H),4.70 (br dd, J=14.5, 5.7 Hz, 1H), 4.58-4.45 (m, 3H), 4.17 (dd, J=9.6,2.6 Hz, 1H), 3.86-3.71 (m, 2H), 2.97-2.82 (m, 2H), 1.27 (t, J=7.5 Hz,3H). LCMS (ESI+): m/z 341.1 (M+H).

Example 41:(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A flask was charged with tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.120 g, 244 umol, 1.00 eq), 1H-pyrazole (24.9 mg, 366 umol, 1.5 eq)and K₃PO₄ (104 mg, 488 umol, 2.00 eq) at 15° C. and purged with N₂.Another flask was charged with Pd₂(dba)₃ (11.2 mg, 12.2 umol, 0.0500 eq)andditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane(11.7 mg, 24.4 umol, 0.100 eq), toluene (2.00 mL) and dioxane (0.400 mL)were added at 15° C., then purged with nitrogen and heated at 120° C.for 0.05 hr, then it cooled to 15° C. The obtained mixture(per-catalyst) was added to the first mixture via syringe. The resultingmixture was stirred at 120° C. for 10 h. LC-MS indicated completeconversion. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=1/1). tert-butyl(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.070 g, 146 umol, 59% yield) was obtained as a brown solid.

Step 2:(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(0.0700 g, 146 umol, 1.00 eq) in HFIP (2 mL) was stirred at 80° C. for12 h under nitrogen atmosphere. LC-MS indicated complete conversion. Thereaction mixture was blown to dryness by nitrogen stream. The residuewas purified by prep-HPLC (formic acid conditions).(S)-12-fluoro-4-(1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(15.3 mg, 34.9 umol, 23% yield, 96.8% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.52 (s, 1H), 9.05 (d,7=1.96 Hz, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.50 (br t, 7=6.11 Hz, 1H),6.94 (br t, 7=9.54 Hz, 1H), 6.67 (dd, 7=8.56, 3.67 Hz, 1H), 6.56 (d,J=1.96 Hz, 1H), 4.95-4.83 (m, 1H), 4.82-4.71 (m, 1H), 4.58-4.45 (m, 2H),4.23 (br dd, 7=9.41, 3.06 Hz, 1H), 4.04 (br s, 1H), 3.92-3.81 (m, 1H).LCMS (ESI+): m/z 379.1 (M+H).

Example 42:(S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a mixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq) and1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(85.2 mg, 383 umol, 1.5 eq) in EtOH (3.5 mL) and water (0.5 mL) wasadded KOAc (50.2 mg, 511 umol, 2.00 eq),4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (18.1mg, 25.6 umol, 18.1 uL, 0.100 eq) in one portion at 25° C. under N₂. Themixture was stirred at 80° C. for 16 h under N₂. LC-MS showed no(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas remained. Several new peaks were shown on LC-MS and the desired MSwas detected. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B %: 10%-40%, 10 min).(S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(13.21 mg, 32.13 umol, 12% yield, 98.9% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.37 (s, 1H), 7.83 (s, 1H), 7.27(t, J=6.3 Hz, 1H), 7.16 (s, 1H), 7.01-6.89 (m, 1H), 6.68 (dd, J=8.7, 3.9Hz, 1H), 4.92-4.82 (m, 1H), 4.79-4.69 (m, 1H), 4.58-4.41 (m, 2H), 4.21(dd, J=9.6, 3.2 Hz, 1H), 4.11-3.96 (m, 1H), 3.92-3.83 (m, 1H), 3.80 (s,3H), 2.37 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).

Example 43:(S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a mixture of 4-bromo-2,3-dimethylpyridine (0.81 g, 4.35 mmol, 1.00eq), KOAc (855 mg, 8.71 mmol, 2.00 eq) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.21 g,8.71 mmol, 2.00 eq) in dioxane (20 mL) was added Pd(dppf)Cl₂ (320 mg,437 umol, 0.100 eq) in one portion at 18° C. under N₂. The mixture wasstirred at 110° C. for 15 h The mixture was evaporated to obtain theproduct. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 0/1, Petroleum ether/Ethylacetate=0:1, R_(f)=0.06).2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(400 mg, 1.72 mmol, 39% yield) was obtained as a white solid.

Step 2:(S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a mixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(50 mg, 127.81 umol, 1.00 eq), NaHCO₃ (53.7 mg, 639 umol, 24.9 uL, 5.00eq) and2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(89.4 mg, 383.4 umol, 3.00 eq) in dioxane (5 mL) and water (0.5 mL) wasadded Pd(dppf)Cl₂ (9.35 mg, 12.8 umol, 0.100 eq) in one portion at 15°C. under N₂. The mixture was stirred at 80° C. for 2 h. LCMS showed thatthe starting material was consumed completely. The mixture wasevaporated to obtain the crude product. The residue was purified byprep-HPLC (neutral condition: column: Nano-micro Kromasil C18 100*30 mm5 urn; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 35%-52%, 10 min).(S)-4-(2,3-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.7 mg, 61.2 umol, 47% yield, 99.4% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.42 (s, 1H), 8.28 (d, J=5.1 Hz,1H), 7.54 (br t, J=6.2 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J=5.0 Hz, 1H),7.00-6.92 (m, 1H), 6.70 (dd, J=8.6, 3.9 Hz, 1H), 4.96-4.87 (m, 1H),4.84-4.74 (m, 1H), 4.54 (t, J=9.4 Hz, 1H), 4.46 (br d, J=5.9 Hz, 1H),4.20 (dd, J=9.5, 3.5 Hz, 1H), 4.09-3.99 (m, 1H), 3.90-3.80 (m, 1H), 2.50(s, 3H), 2.07 (s, 3H). ¹H NMR CD₃OD 400 MHz, δ=ppm 9.71 (s, 1H), 8.65(d, J=6.1 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=6.1 Hz, 1H), 6.99-6.88 (m,1H), 6.69 (dd, J=8.7, 3.8 Hz, 1H), 5.23 (br d, J=14.8 Hz, 1H), 5.02 (brd, J=14.9 Hz, 1H), 4.78 (br s, 1H), 4.63 (t, J=9.5 Hz, 1H), 4.32 (dd,J=9.7, 3.2 Hz, 1H), 4.10 (br d, J=9.5 Hz, 1H), 4.02-3.92 (m, 1H), 2.87(s, 3H), 2.36 (s, 3H). LCMS (ESI+): m/z 418.2 (M+H).

Example 44:(S)-12-fluoro-4-(6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(50.0 mg, 128 umol, 1.00 eq),2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (90.1mg, 383 umol, 3.00 eq) in dioxane (3 mL) and water (0.3 mL) were addedNa₂CO₃ (27.1 mg, 256 umol, 2.00 eq) and Pd(PPh₃)₄ (14.77 mg, 12.78 umol,0.100 eq) at 25° C. The mixture was stirred at 90° C. for 12 h. LC-MSshowed no(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas remained. Several new peaks were shown on LC-MS and the desired MSwas detected. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B %: 20%-50%, 10 min).(S)-12-fluoro-4-(6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(19.10 mg, 44.33 umol, 34% yield, 97.4% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.44 (s, 1H), 8.98 (d, J=2.4 Hz,1H), 8.48 (dd, J=8.7, 2.5 Hz, 1H), 7.67 (s, 1H), 7.50 (br t, J=6.3 Hz,1H), 6.99-6.87 (m, 2H), 6.68 (dd, J=8.6, 3.7 Hz, 1H), 4.94-4.84 (m, 1H),4.83-4.72 (m, 1H), 4.58-4.46 (m, 2H), 4.21 (dd, J=9.7, 3.3 Hz, 1H),4.10-3.98 (m, 1H), 3.94 (br d, J=11.0 Hz, 1H), 3.90 (s, 3H). LCMS(ESI+): m/z 420.2 (M+H).

Example 45:(S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-2-ethyl-4-methylpyridine

To a stirred solution of 2,5-dibromo-4-methylpyridine (2.00 g, 7.97mmol, 1.00 eq.) and ZnEt₂ (1 M, 4.78 mL, 0.6 eq.) in THF (15.0 mL) wasadded Pd(PPh₃)₄ (92.1 mg, 79.7 umol, 0.01 eq.) at 0° C. under N₂. Theresulting mixture was stirred at 70° C. for 1 hr. The mixture was addedto saturated aqueous NaHCO₃ solution (30 mL) and then the mixture wasextracted with EtOAc (20 mL*3) and the combined organic layers weredried over Na₂SO₄ and then concentrated under reduced pressure. Themixture was purified by MPLC (SiO₂, PE/EtOAc=1/0 to 5/1).5-bromo-2-ethyl-4-methylpyridine (720 mg, 3.60 mmol, 45% yield) wasobtained as colourless oil. ¹H NMR CDCl₃ 400 MHz, δ=ppm 8.54 (s, 1H),7.05 (s, 1H), 2.75 (q, J=7.5 Hz, 2H), 2.37 (s, 3H), 1.29 (t, 7=7.6 Hz,3H).

Step 2:2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a stirred solution of 5-bromo-2-ethyl-4-methylpyridine (290 mg, 1.45mmol, 1.00 eq.),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.47 g, 5.80 mmol, 4.00 eq.) and KOAc (285 mg, 2.90 mmol, 2.00 eq) indioxane (15.00 mL) was added Pd(dppf)Cl₂.DCM (237 mg, 290 umol, 0.20 eq)at 15° C. under N₂. The resulting mixture was stirred at 80° C. for 8 h.LCMS showed 5-bromo-2-ethyl-4-methylpyridine was consumed and thedesired mass was detected. The mixture was concentrated under reducedpressure. The mixture was purified by MPLC (SiO₂, PE/EtOAc=1/1 toEtOAc/MeOH=1/1).2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(200 mg, 809 umol, 55% yield) was obtained as brown oil. ¹H NMR CDCl₃400 MHz, δ=ppm 8.76 (s, 1H), 6.96 (s, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.50(s, 3H), 1.27-1.25 (m, 15H).

Step 3:(S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a stirred solution of2-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(126 mg, 511 umol, 4.00 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(50.0 mg, 128 umol, 1.00 eq) and NaHCO₃ (53.7 mg, 639 umol, 24.9 uL,5.00 eq) in dioxane (4.00 mL) and water (0.80 mL) was added Pd(dppf)Cl₂(9.35 mg, 12.8 umol, 0.100 eq) at 15° C. under N₂. The resulting mixturewas stirred at 90° C. for 5 h. The mixture was concentrated underreduced pressure. The mixture was purified by neutral prep-HPLC.(S)-4-(6-ethyl-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(21.7 mg, 49.4 umol, 38% yield, 98.1% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.42 (s, 1H), 8.38 (s, 1H), 7.49(br t, J=6.4 Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.02-6.92 (m, 1H),6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.96-4.86 (m, 1H), 4.83-4.75 (m, 1H), 4.55(t, J=9.3 Hz, 1H), 4.47 (br d, J=6.6 Hz, 1H), 4.21 (dd, J=9.4, 3.3 Hz,1H), 4.05 (br s, 1H), 3.91-3.82 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.17(s, 3H), 1.26 (t, J=7.6 Hz, 3H). LCMS (ESI+): m/z 432.1 (M+H).

Example 46:(S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-bromo-2-(difluoromethyl)pyridine

To a solution of 3-bromopicolinaldehyde (1.00 g, 5.38 mmol, 1.00 eq) inDCM (20 mL) was added DAST (1.73 g, 10.8 mmol, 1.42 mL, 2.00 eq) at 0°C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 h.LC-MS showed 3-bromopicolinaldehyde was consumed completely and one mainpeak with desired mass was detected. The reaction mixture was quenchedby addition of water (20 mL), and then diluted with EtOAc (20 mL) andextracted with EtOAc (20 mL*3). The combined organic layers were washedwith sat. aq. NaCl (30 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=1:0 to 0:1;Petroleum ether:Ethyl acetate=5:1, R_(f)=0.4).3-bromo-2-(difluoromethyl)pyridine (480 mg, 2.31 mmol, 42% yield) wasobtained as a yellow oil.

Step 2:2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 3-bromo-2-(difluoromethyl)pyridine (480 mg, 2.31 mmol,1.00 eq) in dioxane (6 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (762 mg,3.00 mmol, 1.3 eq), KOAc (453 mg, 4.62 mmol, 2.00 eq) and Pd(dppf)Cl₂(169 mg, 231 umol, 0.100 eq) at 25° C. under nitrogen atmosphere. Themixture was stirred at 80° C. for 12 h. LC-MS indicated presence of theremaining starting material. To the mixture was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (586.00 mg,2.31 mmol, 1.00 eq), KOAc (452.96 mg, 4.62 mmol, 2.00 eq) andPd(dppf)Cl₂ (169 mg, 231 umol, 0.100 eq) at 25° C. under nitrogenatmosphere. The mixture was stirred at 80° C. for 2 h. LC-MS indicatedcompleted conversion. The mixture was concentrated in vacuum. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether:Ethylacetate=1:1, R_(f)=0.5).2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(500 mg, crude) was obtained as a yellow solid. ¹H NMR CDCl₃ 400 MHz,δ=ppm 8.78 (br d, 7=3.2 Hz, 1H), 8.17 (br d, 7=7.6 Hz, 1H), 7.43-7.37(m, 1H), 7.26 (t, 7=53.2 Hz, 1H), 1.37 (s, 12H).

Step 3:(S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(156 mg, 614 umol, 4.00 eq) in dioxane (4.5 mL) and water (0.5 mL) wereadded(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(60.0 mg, 153 umol, 1.00 eq), NaHCO₃ (64.4 mg, 767 umol, 29.8 uL, 5.00eq) and Pd(dppf)Cl₂ (11.2 mg, 15.3 umol, 0.100 eq) at 25° C. undernitrogen atmosphere. The mixture was stirred at 80° C. for 5 h. LC-MSshowed2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was filtered and the filtrate was driedunder high vacuum. The residue was purified by prep-HPLC (neutralcondition: column: Waters Xbridge 150*25 5 u; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B %: 25%-35%, 10 min).(S)-4-(2-(difluoromethyl)pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(7.64 mg, 17.2 umol, 11% yield, 98.7% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz, δ=ppm 9.45 (s, 1H), 8.74 (dd, 7=4.6, 1.3Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.66 (dd, 7=7.9, 4.4 Hz, 2H), 7.32 (s,1H), 6.98 (t, 7=10.0 Hz, 1H), 6.90 (t, 7=53.6 Hz, 1H), 6.71 (dd, 7=8.8,4.0 Hz, 1H), 4.97-4.89 (m, 1H), 4.86-4.74 (m, 1H), 4.58-4.43 (m, 2H),4.21 (dd, 7=9.5, 3.5 Hz, 1H), 4.04 (br s, 1H), 3.93-3.83 (m, 1H). LCMS(ESI+): m/z 440.1 (M+H).

Example 47:(S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq) and2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(89.4 mg, 383 umol, 1.50 eq) in water (0.30 mL) and EtOH (2.10 mL) wasadded 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium(18.1 mg, 25.6 umol, 18.1 uL, 0.100 eq) and KOAc (50.2 mg, 511 umol,2.00 eq) at 20° C. The mixture was stirred at 80° C. for 12 h. Themixture was filtered and the filtrate was concentrated under reducedpressure. The residue was purified by prep-HPLC (formic acidconditions).(S)-4-(2,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(4.00 mg, 8.48 umol, 3% yield, 98.3% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-Je 400 MHz, δ=ppm 9.33 (s, 1H), 7.70 (d,J=7.8 Hz, 1H), 7.34 (s, 1H), 7.24 (d, J=7.8 Hz, 1H), 6.95-6.82 (m, 1H),6.65 (dd, J=8.6, 3.9 Hz, 1H), 5.08 (d, J=14.8 Hz, 1H), 4.86 (s, 1H),4.59 (br t, J=9.4 Hz, 2H), 4.29 (dd, J=9.6, 3.1 Hz, 1H), 4.11-3.97 (m,1H), 3.95-3.81 (m, 1H), 2.58 (s, 3H), 2.38 (s, 3H). LCMS (ESI+): m/z418.2 (M+H).

Example 48:(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

Step 1: tert-butyl(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 2-bromo-6-methylpyridine (500 mg, 2.91 mmol, 331 uL,1.00 eq) in THF (20 mL) was added n-BuLi (2.5 M, 1.74 mL, 1.5 eq) at−70° C., the mixture was stirred at −70° C. for 0.5 hr, thentributyl(chloro)stannane (3.78 g, 11.6 mmol, 3.13 mL, 4.00 eq) was addedto the mixture at −70° C., then the mixture was stirred at 20° C. for 12h. TLC (Petroleum ether/Ethyl acetate=5/1 R_(f)=0.5) and LCMS showed thestarting material was consumed completely. The residue was poured intowater (10 mL) and stirred for 5 min. The aqueous phase was extractedwith ethyl acetate (10 mL*2). The combined organic phase was washed withbrine (10 mL), dried with anhydrous Na₂SO₄, filtered, and concentratedin vacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 1/1). Tert-butyl(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.00 g, 2.62 mmol, 90% yield) was obtained as a yellow oil. 1H NMRCDCl3 400 MHz δ=ppm 7.36 (t, J=7.5 Hz, 1H), 7.21-7.15 (m, 1H), 6.96 (d,J=7.7 Hz, 1H), 2.54 (s, 3H), 1.70-1.51 (m, 12H), 1.43-1.22 (m, 6H),0.95-0.87 (td, J=16.9, 7.4 Hz, 9H).

Step 2: tert-butyl(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq) in dioxane (10 mL) was added tert-butyl(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(467 mg, 1.22 mmol, 4.00 eq), CuI (23.3 mg, 122 umol, 0.4 eq), LiCl(25.9 mg, 611 umol, 12.5 uL, 2.00 eq) and Pd(PPh3)4 (35.3 mg, 30.5 umol,0.100 eq) at 20° C. under nitrogen atmosphere. The mixture was stirredat 80° C. for 12 h under nitrogen atmosphere. The mixture was evaporatedto obtain the crude product. The residue was purified by prep-TLC (SiO₂,Petroleum ether:Ethyl acetate=1:2).S)-12-Fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(120 mg, 238 umol, 78% yield) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a mixture of tert-butyl(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 218.46 umol, 1.00 eq) in DCM (10 mL) was added TFA (5.08 g,44.6 mmol, 3.30 mL, 204 eq) in one portion at 18° C. The mixture wasstirred at 18 C for 1.5 h. The mixture was evaporated to obtain thecrude product. The suspension was filtered, the filtrate wasconcentrated and purified by acidic prep-HPLC (formic acid conditions;column: Welch Xtimate C18 150*40 mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 10%-50%, 12 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-12-fluoro-4-(6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(54.7 mg, 120 umol, 54% yield, 98.3% purity, formate salt) was obtainedas an orange solid. 1H NMR DMSO-d6 400 MHz δ=ppm 12.74 (br s, 1H), 9.48(s, 1H), 8.82 (d, J=7.9 Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.82-7.72(m, 2H), 7.16 (d, J=7.6 Hz, 1H), 6.99-6.91 (m, 1H), 6.68 (dd, J=8.6, 3.8Hz, 1H), 4.97-4.88 (m, 1H), 4.86-4.77 (m, 1H), 4.52 (br t, J=9.4 Hz,2H), 4.27 (br dd, J=9.4, 3.1 Hz, 1H), 4.05 (br s, 1H), 3.95-3.84 (m,1H), 2.54 (s, 3H). LCMS (ESI+): m/z 404.2 (M+H).

Example 49:(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 6,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine

To a mixture of 6,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (5.95 g,59.5 mmol, 6.11 mL, 1.00 eq) and 1,2,4-triazol-4-amine (5.00 g, 59.5mmol, 1.00 eq) in toluene (30 mL) was added TsOH.water (56.6 mg, 297umol, 0.005 eq) in one portion at 18° C. The mixture was stirred at 120°C. for 16 h. TLC (Ethyl acetate/Methanol=5/1 R_(f)=0.5) showed that thestarting material was consumed completely. The mixture was evaporatedunder reduced pressure to obtain the crude product. The residue waspurified by re-crystallization from EtOH/TBME (50 mL, v/v=1/5) to givethe pure product. 6,8-Dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (6.60 g,44.5 mmol, 74% yield) was obtained as a white solid. 1H NMR DMSO-d6 400MHz δ=ppm 9.52 (s, 1H), 7.11 (s, 1H), 2.59 (s, 3H), 2.53 (br s, 3H)

Step 2: 4,6-dimethylpyridazin-3-amine

To a mixture of 6,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine (6.60 g,44.5 mmol, 1.00 eq) in MeCN (60 mL) was added2-bromo-1-phenylethan-1-one (8.87 g, 44.5 mmol, 1.00 eq) in one portionat 18° C. The mixture was stirred at 85° C. for 6 h. Most of the solventwas removed by evaporation and water (27 mL) was added to the residuefollowed by addition of NaOH (3.00 g, 75.0 mmol, 1.68 eq) in one portionat 18° C. The mixture was stirred at 100° C. for 16 h. LCMS indicatedformation of the desired product. The suspension was filtered through apad of Celite and the filter cake was washed with water (40 mL*2) at 50°C. The filtrates were cooled to 18° C. and the obtained precipitate wasfiltered off. The filter cake was washed with 30 mL of water and driedin vacuum to give a afford product. 4,6-Dimethylpyridazin-3-amine (2.00g, 16.2 mmol, 36% yield) was obtained as a yellow solid. 1H NMR DMSO-d6400 MHz δ=ppm 6.99 (s, 1H), 5.91 (br s, 2H), 2.33 (s, 3H), 2.03 (s, 3H).

Step 3: 3-bromo-4,6-dimethylpyridazine

To a mixture of 4,6-dimethylpyridazin-3-amine (1.80 g, 14.6 mmol, 1.00eq) in HBr (26.8 g, 159 mmol, 18.0 mL, 48% purity, 10.9 eq) was addedNaNO₂ (1.02 g, 14.8 mmol, 1.01 eq) in water (8 mL) in one portion at 0°C. Then to the mixture was added CuBr (2.94 g, 20.5 mmol, 623 uL, 1.40eq) in HBr (26.8 g, 159 mmol, 18.0 mL, 48% purity, 10.9 eq) in oneportion at 0° C. The mixture was stirred at 100° C. for 5 h The aqueousphase layer was made alkaline with aqueous NaOH (10%) till pH=10. Theaqueous phase was extracted with ethyl acetate (10 mL*2). The combinedorganic phases were washed with brine (10 mL*2), dried with anhydrousNa₂SO₄, filtered, and concentrated in vacuum. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to1/1). Tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.20 g, 6.40 mmol, 43% yield) was obtained as a white solid. 1H NMRDMSO-d6 400 MHz δ=ppm 7.57 (s, 1H), 2.54 (s, 3H), 2.32 (s, 3H).

Step 4: tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateBoc

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 143 umol, 1.00 eq) in dioxane (5 mL) was added3-bromo-4,6-dimethylpyridazine (66.7 mg, 356 umol, 1.06 uL, 2.50 eq),CuI (10.9 mg, 57.0 umol, 0.400 eq), LiCl (12.1 mg, 285 umol, 5.84 uL,2.00 eq) and Pd(PPh3)₄ (16.5 mg, 14.3 umol, 0.100 eq) at 20° C. undernitrogen atmosphere. The mixture was stirred at 80° C. for 12 h undernitrogen atmosphere. The mixture was evaporated under reduced pressureto obtain the product. The residue was purified by prep-TLC (SiO₂,EtOAc:MeOH=10:1). Tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50 mg, 96.42 umol, 67% yield) was obtained as a yellow solid.

Step 5:(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

To a mixture of tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(60.0 mg, 116 umol, 1.00 eq) in DCM (10 mL) was added TFA (2.69 g, 23.6mmol, 1.75 mL, 204 eq) in one portion at 18° C. The mixture was stirredat 18° C. for 1.5 h. LCMS showed 0% of tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateremained. Several new peaks were shown on LCMS and ˜74% of a productwith the desired mass was detected. The mixture was combined withanother batch (from 50 mg of tert-butyl(S)-4-(4,6-dimethylpyridazin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate)and evaporated under reduced pressure. The crude product was dissolvedin DMSO (2 mL) and filtered to remove the insoluble material. Thefiltrate was purified by acidic prep-HPLC (formic acid conditions;column: Welch Xtimate C18 150*40 mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 1%-40%, 12 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(4,6-Dimethylpyridazin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(19.5 mg, 40.7 umol, 96.96% purity, formate salt) was obtained as ayellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.46 (br s, 1H), 7.67 (br s,1H), 7.52 (br s, 1H), 7.47 (s, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.70 (dd,J=8.6, 3.8 Hz, 1H), 4.97-4.88 (m, 1H), 4.86-4.76 (m, 1H), 4.59-4.46 (m,2H), 4.23 (dd, J=9.7, 3.3 Hz, 1H), 4.06 (br s, 1H), 3.92-3.80 (m, 1H),2.63 (s, 3H), 2.18 (s, 3H). LCMS (ESI+): m/z 419.1 (M+H).

Example 50:(S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 214 umol, 1.00 eq), 2-bromo-3-methylpyrazine (44.4 mg, 257umol, 1.20 eq), CuI (16.3 mg, 85.5 umol, 0.400 eq), LiCl (18.1 mg, 428umol, 8.76 uL, 2.00 eq) and Pd(PPh3)₄ (24.7 mg, 21.4 umol, 0.100 eq) indioxane (4.00 mL) was degassed and purged with nitrogen 3 times at 20°C., and then the mixture was stirred at 80° C. for 2.5 h under nitrogenatmosphere. LCMS showed the reaction was complete and the desired masswas detected. The mixture was filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,Petroleum ether:Ethyl acetate=0:1). Tert-butyl(S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.00 mg, crude) was obtained as a yellow solid.

Step 2:(S)-12-fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,31,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 178 umol, 1.00 eq) in DCM (1.50 mL) was added TFA (770 mg,6.75 mmol, 0.500 mL, 37.9 eq) at 20° C. The mixture was stirred at 20°C. for 1 hr. The mixture was concentrated under reduced pressure. Theresidue was combined with other batch (12 mg of final target with 96.3%purity). The mixture was dissolved in DMSO (3 mL). The suspension wasfiltered, the filtrate was concentrated and purified by acidic prep-HPLC(formic acid conditions). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-12-Fluoro-4-(3-methylpyrazin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(30.0 mg, 65.7 umol, 36% yield, 98.6% purity, formate salt) was obtainedas a yellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.44 (s, 1H), 8.62-8.45(m, 2H), 7.69 (br t, J=6.2 Hz, 1H), 7.48 (s, 1H), 7.04-6.87 (m, 1H),6.68 (dd, J=8.6, 3.7 Hz, 1H), 4.96-4.86 (m, 1H), 4.84-4.73 (m, 1H),4.57-4.40 (m, 2H), 4.20 (dd, J=9.5, 3.5 Hz, 1H), 4.03 (br s, 1H),3.88-3.75 (m, 1H), 2.40 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).

Example 51:(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-fluoro-3-methyl-2-(trimethylstannyl)pyridine

2-bromo-5-fluoro-3-methylpyridine (200 mg, 1.05 mmol, 1.00 eq),trimethyl(trimethylstannyl)stannane (690 mg, 2.11 mmol, 437 uL, 2.00 eq)and Pd(PPh₃)₄ (122 mg, 105 umol, 0.100 eq) were taken up into amicrowave tube in dioxane (10 mL) at 18° C. under N2. The sealed tubewas heated at 110° C. for 3 h under microwave. LCMS showed the reactionwas complete. The suspension was filtered through a pad of Celite andthe filter cake was washed with dioxane (1 mL).5-Fluoro-3-methyl-2-(trimethylstannyl)pyridine (288 mg, 1.05 mmol, 99%yield) in dioxane (11 mL) was used for the next step without furtherpurification.

Step 2: tert-butyl(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407.08 umol, 1.00 eq) in dioxane (10 mL) was added5-fluoro-3-methyl-2-(trimethylstannyl)pyridine (288 mg, 1.05 mmol, 2.59eq) in dioxane (11 mL), CuI (31.0 mg, 163 umol, 0.400 eq), LiCl (34.5mg, 814 umol, 16.7 uL, 2.00 eq) and Pd(PPh₃)₄ (47.0 mg, 40.7 umol, 0.100eq) at 20° C. under nitrogen atmosphere. The mixture was stirred at 80°C. for 2 h under nitrogen atmosphere. LCMS showed tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely. Several new peaks were shown on LCMS and thedesired mass was detected. The mixture was evaporated under reducedpressure to obtain the crude product. The residue was purified byprep-TLC (SiO₂, Petroleum ether:Ethyl acetate=0:1). tert-butyl(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 384 umol, 94% yield) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

To a solution of tert-butyl(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 288 umol, 1.00 eq) in DCM (3 mL) was added TFA (1.54 g, 13.5mmol, 1.00 mL, 47.0 eq) at 20° C. The mixture was stirred at 20° C. for2 hr TLC (SiO₂, PE:EtOAc=0:1) indicated tert-butyl(S)-12-fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely. The reaction mixture was concentrated underreduced pressure. The crude product was dissolved in MeCN (2 mL) andfiltered to remove the insoluble material. The the filtrate wasevaporated and purified by acidic prep-HPLC (formic acid conditions;column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 15%-45%, 12 min). The product-containing fractionwas concentrated under reduced pressure to remove most of MeCN at 30° C.and the aqueous phase was lyophilized.(S)-12-Fluoro-4-(5-fluoro-3-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(33.4 mg, 78.7 umol, 27% yield, 99.3% purity, formate salt) was obtainedas white solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.43 (s, 1H), 8.45 (d,J=2.4 Hz, 1H), 7.72 (dd, J=9.6, 2.3 Hz, 1H), 7.62-7.53 (m, 1H), 7.35 (s,1H), 6.96 (t, J=9.4 Hz, 1H), 6.75-6.65 (m, 1H), 4.97-4.85 (m, 1H),4.84-4.71 (m, 1H), 4.59-4.44 (m, 2H), 4.28-4.17 (m, 1H), 4.05 (br s,1H), 3.89-3.75 (m, 1H), 2.20 (s, 3H). LCMS (ESI+): m/z 422.2 (M+H).

Example 52: General Procedure A. Preparation of(S)-4-(3,5-dimethylisoxazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(80.0 mg, 205 umol, 1.00 eq) in dioxane (2.00 mL) and water (0.200 mL)was added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(57.6 mg, 409 umol, 2.00 eq), Na₂CO₃ (43.4 mg, 409 umol, 2.00 eq) andPd(dppf)Cl₂ (15.0 mg, 20.4 umol, 0.100 eq) at 20° C. The mixture wasstirred at 80° C. for 2 h under nitrogen atmosphere. Reaction progresswas monitored by LC-MS. The reaction mixture was filtered, the filtratewas concentrated. The residue was dissolved in MeOH (8 mL) andsilica-thiol (500 mg, modified silicon gel for eliminating Pd, irregularsilica gel, 100-200 mesh, Chlorides (Cl), %≤0.004, particle sizedistribution 45-75 um) was added at 20° C. and stirred at 20° C. for 2h. The suspension was filtered and the filtrate was evaporated andpurified by neutral prep-HPLC (column: Nano-micro Kromasil C18 80*25 mm3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 30%-50%, 10 min).The product-containing fraction was concentrated under reduced pressureto remove most of MeCN at 30° C. and the residue was lyophilized.(S)-4-(3,5-dimethylisoxazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(58.0 mg, 140 umol, 68% yield, 98.4% purity) was obtained as a whitesolid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.41 (s, 1H), 7.52 (br s, 1H), 7.35(s, 1H), 6.98 (t, J=9.5 Hz, 1H), 6.71 (dd, J=8.6, 3.7 Hz, 1H), 4.95-4.87(m, 1H), 4.83-4.74 (m, 1H), 4.56-4.49 (m, 1H), 4.45 (br d, J=6.5 Hz,1H), 4.21 (dd, J=9.5, 3.5 Hz, 1H), 4.05 (br s, 1H), 3.92-3.77 (m, 1H),2.36 (s, 3H), 2.19 (s, 3H). LCMS (ESI+): m/z 408.1 (M+H)

Compounds 49, 58, 72, 77-78, 91, 94, 96, 103, 105-106, 108-109, 111-112,114-118, and 142 were prepared according to General Procedure A usingthe suitable starting materials, precursors, intermediates, andreagents.

Cmpd No. Compound Name Compound Structure Spectral Data 72(S)-4-(1-ethyl-1H- pyrazol- 5-y1)-12-fluoro-7a,8,13,14- tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- [4',3':1,6]pyrido[3,2-fg] [1,4]oxazonine

1H NMR DMSO-d6 400 MHz δ = ppm 9.42 (s, 1H), 7.63 (br t, J = 6.4 Hz,1H), 7.50 (d, J = 1.5 Hz, 1H), 7.34 (s, 1H), 6.99-6.90 (m, 1H), 6.68(dd, J = 8.7, 3.9 Hz, 1H), 6.43 (d, J = 1.5 Hz, 1H), 4.93-4.84 (m, 1H),4.82-4.72 (m, 1H), 4.56-4.41 (m, 2H), 4.19 (dd, J = 9.6, 3.6 Hz, 1H),4.08 (q, J = 7.2 Hz, 2H), 4.02 (br s, 1H), 3.90-3.78 (m, 1H), 1.23 (t, J= 7.2 Hz, 3H). LCMS (ESI+): m/z 407.1 (M + H). 49(S)-4-(12-fluoro-7a,8,13,14- tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonin-4-yl)-3-methylbenzonitrile

1H NMR DMSO-d6 400 MHz δ = ppm 9.43 (s, 1H), 7.81 (s, 1H), 7.75- 7.69(m, 1H), 7.63-7.55 (m, 2H), 7.34 (s, 1H), 6.98 (dd, J = 10.1, 8.9 Hz,1H), 6.71 (dd, J = 8.6, 3.7 Hz, 1H), 4.98-4.87 (m, 1H), 4.84-4.75 (m,1H), 4.59-4.43 (m, 2H), 4.21 (dd, J = 9.4, 3.5 Hz, 1H), 4.09-4.00 (m,1H), 3.92-3.83 (m, 1H), 2.23 (s, 3H). LCMS (ESI+): m/z 428.1 (M + H) 78(S)-4-(2-(difluoromethoxy) pyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro[4,3- fg][1,4] oxazonine

1H NMR DMSO-d6 400 MHz δ = ppm 9.45 (s, 1H), 8.40 (dd, J = 7.5, 1.5 Hz,1H), 8.26 (dd, J = 4.8, 1.7 Hz, 1H), 7.73 (t, J = 72.4 Hz, 1H), 7.66 (brt, J = 6.4 Hz, 1H), 7.56 (s, 1H), 7.40 (dd, J = 7.5, 5.0 Hz, 1H), 6.97(t, J = 9.5 Hz, 1H), 6.70 (dd, J = 3.7, 8.6 Hz, 1H), 4.97-4.87 (m, 1H),4.86-4.77 (m, 1H), 4.54 (t, J = 9.5 Hz, 1H), 4.46 (br s, 1H), 4.21 (dd,J = 9.5, 3.4 Hz, 1H), 4.06 (br s, 1H), 3.92-3.80 (m, 1H). LCMS(ESI+):m/z 456.1 (M + H). 77 (S)-12-fluoro-4-(2- methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro[4,3-fg] [1,4] oxazonine

1H NMR CDCl3 400 MHz δ = ppm 8.93 (s, 1H), 8.32 (br d, J = 7.1 Hz, 1H),8.15 (br d, J = 3.9 Hz, 1H), 7.57 (s, 1H), 6.99 (dd, J = 7.0, 5.2 Hz,1H), 6.85 (br t, J = 9.4 Hz, 1H), 6.65 (dd, J = 8.6, 3.7 Hz, 1H), 5.36(br s, 1H), 5.07 (br dd, J = 14.6, 6.4 Hz, 1H), 4.91-4.77 (m, 1H), 4.69-4.50 (m, 2H), 4.18-4.28 (m, 1H), 3.97 (s, 3H), 3.95-3.76 (m, 2H). LCMS(ESI+): m/z 420.1 (M + H). 58 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro[4,3- fg][1,4]oxazonin-4-yl)- N,N,4-trimethylpyrimidine-2-carboxamide

1H NMR DMSO-d6 400 MHz δ = ppm 9.58 (s, 1H), 8.82 (s, 1H), 7.98 (br s,1H), 7.68 (s, 1H), 6.99 (t, J = 9.2 Hz, 1H), 6.72) (dd, J = 8.4, 3.6 Hz,1H), 5.03-4.91 (m, 1H), 4.83 (br d, J = 8.4 Hz, 1H), 4.62-4.51 (m, 2H),4.23 (br d, J = 6.4 Hz, 1H), 4.06 (br s, 1H), 3.93-3.84 (m, 1H), 3.04(s, 3H), 2.86 (s, 3H), 2.44 (s, 3h). LCMS (ESI+): m/z 476.2 (M + H). 96(S)-4-(2-ethylpyridin-3-yl)- 12-fluoro-7a,8,13,14- tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro [4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.41 (s, 1H), 8.53 (dd, J = 4.9, 1.5 Hz,1H), 7.68 (dd, J = 7.6, 1.7 Hz, 1H), 7.55-7.47 (m, 1H), 7.33- 7.22 (m,2H), 7.00-6.90 (m, 1H), 6.73-6.64 (m, 1H), 4.95-4.84 (m, 1H), 4.81-4.72(m, 1H), 4.57-4.42 (m, 2H), 4.25-4.16 (m, 1H), 4.07- 3.97 (m, 1H),3.89-3.78 (m, 1H), 2.60 (q, J = 7.4 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H).LCMS (ESI+): m/z 418.0 (M + H). 105 (S)-12-fluoro-4-(2-methoxy-6-methylpyridin- 3-yl)-7a,8,13,14-tetrahydro- 7H-[1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro [4,3-fg ][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.40 (d, J = 2.3 Hz, 1H), 8.17 (d, J =7.6 Hz, 1H), 7.55 (s, 1H), 7.47 (br t, J = 6.5 Hz, 1H), 7.00- 6.89 (m,2H), 6.69 (dd, J = 8.7, 3.8 Hz, 1H), 4.95-4.86 (m, 1H), 4.83- 4.74 (m,1H), 4.58-4.42 (m, 2H), 4.22 (dd, J = 9.5, 3.5 Hz, 1H), 4.10- 3.99 (m,1H), 3.89 (s, 3H), 3.85- 3.78 (m, 1H), 2.45 (s, 3H). LCMS (ESI+): m/z434.1 (M + H). 106 (S)-12-fluoro-4-(6- methoxy-2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro- 7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro [4,3- fg][1,4] oxazonine

¹H NMR CDCl₃ 400 MHz δ = 8.88 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.03(s, 1H), 6.87 (t, J = 9.5 Hz, 1H), 6.67 (dd, J = 8.7, 3.9 Hz, 1H), 6.61(d, J = 8.4 Hz, 1H), 5.16- 5.03 (m, 2H), 4.83 (br d, J = 9.3 Hz, 1H),4.64 (t, J = 9.4 Hz, 1H), 4.58 (dd, J = 9.9, 4.2 Hz, 1H), 4.25 (dd, J =9.7, 3.3 Hz, 1H), 4.00 9 , 3H), 3.98-3.89 (m, 1H), 3.87-3.77 (m, 1H),2.38 (s, 3H). LCMS (ESI+): m/z 434.2 (M + H) 114 (S)-12-fluoro-4-(2-(trifluoromethyl) pyrimidin- 5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro [4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.86 (s, 2H), 9.45 (s, 1H), 8.22 (s, 1H),7.95 (br s, 1H), 7.03-6.89 (m, 1H), 6.78-6.65 (m, 1H), 4.97- 4.88 (m,1H), 4.87-4.79 (m, 1H), 4.53 (br t, J = 9.3 Hz, 2H), 4.25- 4.18 (m, 1H),4.09-4.00 (m, 1H), 3.99-3.91 (m, 1H). LCMS (ESI+): m/z 459.2 (M + H).115 (S)-12-fluoro-4-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-5-yl)-7a,8,13,14- tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro [4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.47 (s, 1H), 7.81 (br t, J = 6.2 Hz,1H), 7.47 (s, 1H), 7.02 (s, 1H), 7.00-6.91 (m, 1H), 6.70 (dd, J = 8.6,3.9 Hz, 1H), 4.98-4.88 (m, 1H), 4.86-4.76 (m, 1H), 4.58-4.44 (m, 2H),4.21 (dd, J = 9.6, 3.5 Hz, 1H), 4.10-3.99 (m, 1H), 3.92 (s, 3H),3.91-3.84 (m, 1H). LCMS (ESI+): m/z 461.2 (M + H). 116(S)-12-fluoro-4-(6- morpholinopyridin-3-yl)- 7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.41 (s, 1H), 8.96 (d, J = 2.3 Hz, 1H),8.36 (dd, J = 9.0, 2.4 Hz, 1H), 7.60 (s, 1H), 7.41 (br t, J = 6.5 Hz,1H), 6.97-6.89 (m, 2H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 4.92-4.82 (m,1H), 4.80-4.68 (m, 1H), 4.56- 4.46 (m, 2H), 4.21 (dd, J = 9.5, 3.2 Hz,1H), 4.07-3.86 (m, 2H), 3.76- 3.67 (m, 4H), 3.53-3.46 (m, 4H). LCMS(ESI+): m/z 475.2 (M + H). 117 (S)-12-fluoro-4-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)-7a,8,13,14- tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.41 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H),8.37-8.30 (m, 1H), 8.15 (s, 1H), 7.27 (s, 1H), 7.44-7.33 (m, 1H),7.00-6.85 (m, 2H), 6.71-6.63 (m, 1H), 4.92-4.83 (m, 1H), 4.81- 4.71 (m,1H), 4.57-4.46 (m, 2H), 4.25-4.17 (m, 1H), 4.09-3.99 (m, 1H), 3.96-3.86(m, 1H), 3.57-3.52 (m, 4H), 2.43 (br t, J = 4.9 Hz, 4H), 2.24 (s, 3H).LCMS (ESI+): m/z 488.2 (M + H). 118 (S)-12-fluoro-4-(2-(4-methylpiperazin-1- yl)pyrimidin-5-yl)- 7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.42 (s, 1H), 9.13 (s, 1H), 8.15 (s, 1H),7.66 (s, 1H), 7.48 (br t, J = 6.4 Hz, 1H), 6.99-6.90 (m, 1H), 6.73-6.63(m, 1H), 4.91-4.83 (m, 1H), 4.80-4.71 (m, 1H), 4.56-4.42 (m, 2H),4.25-4.16 (m, 1H), 4.08- 3.97 (m, 1H), 3.95-3.86 (m, 1H), 3.82-3.75 (m,4H), 2.42-2.37 (m, 4H), 2.23 (s, 3H). LCMS (ESI+): m/z 489.2 (M + H).112 (S)-12-fluoro-4-(6- (trifluoromethyl) pyridin-3-yl)-7a,8,13,14-tetrahydro- 7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.56 (s, 1H), 9.51 (s, 1H), 8.97 (d, J =7.0 Hz, 1H), 8.51 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.89(s, 1H), 6.97 (t, J = 9.5 Hz, 1H), 6.70 (dd, J = 8.6, 3.7 Hz, 1H),4.98-4.90 (m, 1H), 4.88-4.79 (m, 1H), 4.55 (t, J = 9.3 Hz, 2H), 4.23(dd, J = 9.7, 3.0 Hz, 1H), 4.06 (s, 1H), 4.01-3.92 (m, 1H). LCMS (ESI+):m/z 458.1 (M + H). 109 (S)-4-(2-ethoxypyrimidin-5-yl)-12-fluoro-7a,8,13,14- tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.45 (s, 1H), 9.35 (s, 2H), 7.82 (s, 1H),7.60 (br s, 1H), 6.98-6.89 (m, 1H), 6.72-6.63 (m, 1H), 4.94- 4.85 (m,1H), 4.82-4.72 (m, 1H), 4.60-4.48 (m, 2H), 4.40 (q, J = 7.1 Hz, 2H),4.26-4.17 (m, 1H), 4.08- 3.86 (m 2H), 1.36 (t, J = 7.1 Hz, 3H). LCMS(ESI+): m/z 435.1 (M + H). 94 (S)-12-fluoro-4-(6-methylpyridin-3-yl)-7a,8,13, 14-tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.45 (s, 1H), 9.22 (s, 1H), 8.46 (dd, J =8.1, 2.3 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (m, 1H), 7.33 (d, J = 8.2 Hz,1H), 6.95 (dd, J = 10.0, 8.9 Hz, 1H), 6.68 (dd, J = 8.6, 3.8 Hz, 1H),4.95-4.85 (m, 1H), 4.83- 4.74 (m, 1H), 4.58-4.49 (m, 2H), 4.24-4.18 (m,1H), 4.08-3.99 (m, 1H), 3.97-3.90 (m, 1H), 2.52 (br s, 3H). LCMS (ESI+):m/z 404.1 (M + H). 108 (S)-5-(12-fluoro- 7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4]oxazonin-4-yl)-N,N- dimethylpyrimidin-2-amine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.42 (s, 1H), 9.12 (s, 2H), 7.64 (s, 1H),7.44 (br t, J = 6.5 Hz, 1H), 6.99-6.90 (m, 1H), 6.67 (dd, J = 8.5, 3.9Hz, 1H), 4.92-4.83 (m, 1H), 4.81-4.72 (m, 1H), 4.57-4.45 (m, 2H), 4.21(dd, J = 9.8, 3.2 Hz, 1H), 4.09-3.97 (m, 1H), 3.96-3.87 (m, 1H), 3.17(s, 6H). LCMS (ESI+): m/z 434.1 (M + H). 111 (S)-12-fluoro-4-(5-fluoro-2-methoxypyridin-3-yl)- 7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.44 (s, 1H), 8.53-8.40 (m, 1H), 8.14 (s,1H), 7.77 (s, 1H), 7.72- 7.60 (m, 1H), 7.01-6.91 (m, 1H), 6.74-6.65 (m,1H), 4.96-4.86 (m, 1H), 4.85-4.74 (m, 1H), 4.58-4.42 (m, 2H), 4.27-4.16(m, 1H), 4.11- 3.98 (m, 1H), 3.94 (s, 3H), 3.87- 3.78 (m, 1H). LCMS(ESI+): m/z 438.1 (M + H). 103 (S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H- [1,2,4]triazolo [4',3':1,6]pyrido[3,2-b]benzofuro[4,3- fg][1,4] oxazonin-4-yl)-N,N- dimethylpyrimidin-2-amine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.38 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H),8.28 (dd, J = 9.0, 2.4 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.32 (t, J =6.4 Hz, 1H), 6.95-6.86 (m, 1H), 6.70 (d, J = 9.0 Hz, 1H), 6.65 (dd, J =8.6, 4.0 Hz, 1H), 4.89-4.81 (m, 1H), 4.79-4.68 (m, 1H), 4.55- 4.43 (m,2H), 4.19 (dd, J = 9.6, 3.2 Hz, 1H), 4.07-3.95 (m, 1H), 3.94- 3.84 (m,1H), 3.05 (s, 6H). LCMS (ESI+): m/z 433.1 (M + H). 91(S)-12-fluoro-4-(pyrimidin- 5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo [4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4]oxazonine

¹H NMR DMSO-d₆ 400 MHz δ = ppm 9.61 (s, 2H), 9.51 (s, 1H), 9.12 (s, 1H),8.00 (s, 1H), 7.81 (t, J = 6.0 Hz, 1H), 6.97 (t, J = 9.6 Hz, 1H), 6.70(dd, J = 8.6, 3.7 Hz, 1H), 4.55 (t, J = 9.3 Hz, 2H), 4.23 (dd, J = 9.6,3.0 Hz, 1H), 4.05 (s, 1H), 4.01-3.91 (m, 1H), 2.88-2.64 (m, 1H). LCMS(ESI+): m/z 391.1 (M + H). 142 (S)-12-fluoro-4-(1H-pyrazol-5-yl)-7a,8,13,14- tetrahydro-7H- [1,2,4]triazolo[4',3':1,6]pyrido[3,2- b]benzofuro[4,3- fg][1,4] oxazonine

¹H NMR ET20970-391-P1C12 DMSO-d₆ 400 MHz δ = ppm 9.39 (s, 1H), 7.81 (s,1H), 7.67 (br s, 1H), 7.32 (br s, 1H), 7.20 (br s, 1H), 6.92 (dd, J =10.4, 8.8 Hz, 1H), 6.66 (dd, J = 8.8, 4.0 Hz, 1H), 4.98-4.89 (m, 1H),4.87-4.78 (m, 1H), 4.59-4.48 (m, 2H), 4.23 (dd, J = 9.6, 3.6 Hz, 1H),4.13-4.00 (m, 1H), 3.97-3.89 (m, 1H). LCMS (ESI+): m/z 379.1 (M + H).

Example 53:(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 214 umol, 1.00 eq) and 3-fluoro-2-iodo-pyridine (62.0 mg, 278umol, 1.30 eq) in dioxane (6 mL) was added LiCl (18.1 mg, 428 umol, 8.76uL, 2.00 eq), CuI (16.3 mg, 85.5 umol, 0.400 eq) and Pd(PPh3)4 (24.7 mg,21.4 umol, 0.100 eq) under nitrogen atmosphere. The mixture was stirredat 80° C. for 8 h under nitrogen atmosphere. The reaction mixture wasfiltered, the obtained solid was washed with MeOH (20 mL) and driedunder reduced pressure to give 82 mg of the product. The filtrate wasconcentrated under reduced pressure and the residue was purified byprep-TLC (SiO2, EtOAc:MeOH=10:1) to give additional 10 mg of the productwhich was combined with the first batch, tert-butyl(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(92.0 mg, 181 umol, 84% yield) was obtained as a yellow oil.

Step 2:(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

A mixture of tert-butyl(S)-12-fluoro-4-(3-fluoropyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(92.0 mg, 181 umol, 1.00 eq) and HFIP (5 mL) was stirred at 80° C. for 8h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (formic acid conditions). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-12-Fluoro-4-(3-fluoropyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(23.0 mg, 50.3 umol, 27% yield, 99.2% purity, formate salt) was obtainedas a yellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.45 (s, 1H), 8.49 (d,J=3.1 Hz, 1H), 7.85-7.70 (m, 2H), 7.56-7.45 (m, 2H), 6.93 (t, J=9.4 Hz,1H), 6.66 (dd, J=8.5, 3.2 Hz, 1H), 4.93-4.85 (m, 1H), 4.79 (br s, 1H),4.57-4.37 (m, 2H), 4.25-4.15 (m, 1H), 4.01 (br s, 1H), 3.88-3.75 (m,1H). LCMS (ESI+): m/z 408.1 (M+H).

Example 54:(S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate salt Step 1: Step 1: tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Tributyl (2-pyridyl) stannane (56.2 mg, 0.153 mmol) was added to asolution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 50.0 mg, 0.102 mmol) and tetrakis(triphenylphosphine)palladium(O) (35.3 mg, 0.0306 mmol) in toluene (1.00 mL) under nitrogen.The mixture was stirred at 115° C. for 16 h and diluted with sat. aq.NaCl (15.0 mL). The aqueous phase was extracted with DCM (3×15 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (12 g cartridge) eluting with EtOAcin hexanes (0-100%) to afford the tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatecompound as an oil (31.3 mg, 63%). 1H NMR (500 MHz, CDCl3) δ 9.21 (d,J=8.0 Hz, 1H), 8.72 (s, 1H), 8.67 (d, J=3.8 Hz, 1H), 8.22 (s, 1H), 7.85(td, J=7.8, 1.9 Hz, 1H), 7.35-7.27 (m, 1H), 6.60 (s, 1H), 6.53 (s, 1H),5.37 (s, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 4.48 (t, J=8.8 Hz, 1H), 4.26(dd, J=9.7, 1.2 Hz, 1H), 4.18-4.11 (m, 1H), 3.97-3.86 (m, 1H), 1.35 (s,9H). m/z (ES+) [M+H]+: 490.11. HPLC tR (A05)=2.44 min.

Step 2:(S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(31.3 mg, 0.0639 mmol) in HFIP (2.00 mL) was stirred at 100° C. for 5 h.The solution was concentrated under reduced pressure, and the residuewas purified by preparative HPLC (BEH C18 30×150 mm AmBicarb/ACN 35-55%)to afford(S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineas a solid (13.0 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H),9.01 (d, J=8.2 Hz, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.31 (d, J=1.7 Hz, 1H),7.90 (t, J=7.8 Hz, 1H), 7.79 (t, J=6.6 Hz, 1H), 7.30 (dd, J=7.6, 4.7 Hz,1H), 6.95 (t, J=9.8 Hz, 1H), 6.68 (dd, J=9.7, 3.6 Hz, 1H), 4.87 (tdd,J=16.6, 11.3, 5.2 Hz, 2H), 4.54 (dd, J=20.7, 10.4 Hz, 2H), 4.25 (d,J=11.4 Hz, 1H), 4.05 (s, 1H), 3.88 (t, J=10.9 Hz, 1H). m/z (ES+) [M+H]+:390.2. HPLC tR (A05)=2.73 min.

Step 3:(S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemonomesylate

Methanesulfonic acid (0.00217 mL, 0.0334 mmol) was added to a suspensionof(S)-12-fluoro-4-(pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(13.0 mg, 0.0334 mmol) in MeCN (2.00 mL). The mixture was stirred at rtfor 1 h. The mixture was concentrated under reduced pressure to providethe title compound as a solid (15.2 mg, 94%). 1H NMR (500 MHz, DMSO-d6)δ 9.67 (s, 1H), 8.74 (d, J=4.8 Hz, 1H), 8.66-8.47 (m, 3H), 8.08 (t,J=7.5 Hz, 1H), 7.49-7.42 (m, 1H), 6.99 (t, J=9.0 Hz, 1H), 6.73 (d, J=6.9Hz, 1H), 4.98 (dd, J=25.9, 15.4 Hz, 2H), 4.65 (s, 1H), 4.56 (t, J=9.0Hz, 1H), 4.25 (d, J=6.9 Hz, 1H), 4.11 (s, 1H), 3.99 (s, 1H), 2.30 (s,3H). m/z (ES+) [M+H-MsOH]+: 393.2, HPLC tR (B05)=1.33 min.

Example 55: General Procedure E. Preparation of(S)-12-fluoro-N,N-dimethyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxamideStep 1: tert-butyl(S)-12-fluoro-4-vinyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 300 mg, 0.611 mmol), potassium vinyltrifluoroborate (164mg, 1.22 mmol), Pd(dppf)Cl₂ (44.7 mg, 0.0611 mmol), and NaHCO₃ (256 mg,3.05 mmol) in 1,4-dioxane/water (5.00/0.500 mL) deoxygenated by applyingvacuum and refilling with nitrogen. Two additional deoxygenation cycleswere applied. The mixture was stirred at 90° C. for 4 h. The mixture wasdiluted with water (15.0 mL) at room temperature, and the aqueous phasewas extracted with EtOAc (4×25.0 mL). The combined organic layers werewashed with sat. aq. NaCl (15.0 mL), dried over MgSO4, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (24 g cartridge) eluting with MeOH in DCM (0-15%) toprovide tert-butyl(S)-12-fluoro-4-vinyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (0.258 g, 96%). ES+[M]+: 438.37; HPLC tR (A05)=2.27 min.

Step 2: tert-butyl(S)-12-fluoro-4-formyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

NaIO₄ (755 mg, 3.53 mmol) and 2,6-lutidine (0.137 mL, 1.18 mmol) weresequentially added to a stirred solution of aq. OsO₄ (0.187 mL, 29.4μmol, 4.00%) and tert-butyl(S)-12-fluoro-4-vinyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(258 mg, 0.588 mmol) in 1,4-dioxane/water (6.00 mL/2.00 mL) under N2.The mixture was stirred at room temperature for 4.5 h. Water (15.0 mL)and EtOAc (20.0 mL) were added. The aqueous phase was extracted withEtOAc (3×30 mL). The combined organic layers were washed with sat. aq.NaCl (15.0 mL), dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatography(24 g cartridge) with EtOAc in hexanes (10-90%) to afford tert-butyl(S)-12-fluoro-4-formyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(159 mg, 61%) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.72(s, 1H), 7.66 (s, 1H), 6.72-6.47 (m, 2H), 5.34 (bs, 1H), 4.74 (bs, 1H),4.63 (bs, 1H), 4.48 (dd, J=9.6, 7.8 Hz, 1H), 4.27 (dd, J=9.7, 1.4 Hz,1H), 4.01 (t, J=11.5 Hz, 1H), 3.96-3.85 (m, 1H), 1.36 (s, 9H). m/z (ES+)[M+H]+: 441.62; HPLC tR (A05)=2.13 min.

Step 3:(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid

2-Methyl-2-butene (0.373 mL, 3.52 mmol) was added to a solution oftert-butyl(S)-12-fluoro-4-formyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(155 mg, 0.352 mmol) in tBuOH (4.50 mL). A solution of NaClO₂ (95.5 mg,1.06 mmol) and NaH₂PO₄ (76.0 mg, 0.633 mmol) in water (3.00 mL) wasadded dropwise. The mixture was stirred at room temperature for 2 h. Themixture was concentrated under reduced pressure. Water (10.0 mL) wasadded, and the aqueous phase was extracted with EtOAc (4×20.0 mL). Thecombined organic layers were washed with sat. aq. NaCl (8.00 mL), driedover MgSO4, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (12 g, cartridge) withMeOH in DCM (0-30%) to afford(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid as a solid (128 mg, 80%). m/z (ES+) [M]+: 456.73; HPLC tR(A05)=1.98 min

Step 4: tert-butyl(S)-4-(dimethylcarbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

N,N-Diisopropylethylamine (22.9 μL, 0.131 mmol) was added to a solutionof(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid (30.0 mg, 0.0657 mmol) and dimethylamine hydrochloride (8.04 mg,0.0986 mmol) in DMF (1.00 mL). HATU (50.0 mg, 0.131 mmol) was added. Themixture was stirred at room temperature for 2 h. Reaction completion wasmonitored by chromatography. The mixture was concentrated under reducedpressure. Water (10.0 mL) was added, and the aqueous phase was extractedwith EtOAc (3×20.0 mL). The combined organic layers were washed withsat. aq. NaCl (8.00 mL), dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (4 g, cartridge) with MeOH in DCM (0-10%) to providetert-butyl(S)-4-(dimethylcarbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (25.0 mg, 79%). m/z (ES+) [M+H]+: 484.78; HPLC tR (A05)=2.05min.

Step 5:(S)-12-fluoro-N,N-dimethyl-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxamide

A solution of tert-butyl(S)-4-(dimethylcarbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(25.0 mg, 0.0517 mmol) in HFIP (1.00 mL) was heated to 100° C. for 2 h.The mixture was concentrated under reduced pressure. The residue waspurified by preparative HPLC (Gemini C18 30×100 mm AmBicarb/ACN 25-45%)to afford the title compound as a solid (4.50 mg, 23%). 1H NMR (400 MHz,CD3OD) δ 9.30 (s, 1H), 7.51 (s, 1H), 6.86 (dd, J=10.3, 8.7 Hz, 1H), 6.62(dd, J=8.7, 3.9 Hz, 1H), 5.05 (d, J=14.8 Hz, 1H), 4.86 (d, J=14.6 Hz,1H), 4.57 (t, J=9.3 Hz, 2H), 4.27 (dd, J=9.6, 3.3 Hz, 1H), 3.99 (ddd,J=12.9, 9.8, 4.8 Hz, 1H), 3.92-3.77 (m, 1H), 3.13 (s, 3H), 2.94 (s, 3H).m/z (ES+) [M]+: 383.38; HPLC tR (A05)=1.83 min.

Compounds 38 and 64 were prepared according to General Procedure E usingthe suitable starting materials, precursors, intermediates, andreagents.

Cmpd No. Compound Name Structure Spectral Data 64 (S)-12-fluoro-N -

1H NMR (500 MHz, MeOD) δ 9.31 (s, 1H), methyl-N- 7.49 (s, 1H), 6.86 (dd,J =10.3, 8.7 Hz, 1H), (tetrahydro-2H 6.62 (dd, J = 8.7, 3.8 Hz, 1H),5.05 (d, J = pyran-4-yl)- 14.8 Hz, 1H), 4.86 (m, 2H), 4.56 (t, J = 9.37a,8,13,14- Hz, 2H), 4.27 (dd, J = 9.6, 3.2 Hz, 1H), 4.09−tetrahydro-7H- 3.93 (m, 2H), 3.85 (t, J = 11.2 Hz, 2H), [1,2,4]triazolo3.56 (bs, 1H), 3.11−2.72 (m, 3H), 2.20− [4',3':1,6]pyrido[3,2- 2.10 (m,1H), 1.98−1.85 (m, 2H), 1.79 (bs, b]benzofuro [4,3- 2H) (rotamers); m/z(ES+) [M]+: 453.35; fg][1,4] oxanzonine- LC-MS (A05) tR = 1.85 min.4-carboxamide 38 (S)-12-fluoro-N-

1H NMR (500 MHz, DMSO) δ 9.42 (s, 1H), methyl-N-(2,2,2- 7.79 (s, 1H),7.45 (s, 1H), 6.96 (dd, J =10.2, trifluoroethyl)- 8.8 Hz, 1H), 6.69 (dd,J =8.7, 3.8 Hz, 1H), 7a,8,13,14- 4.90 (d, J = 15.0 Hz, 1H), 4.80 (d, J =15.4 tetrahydro-7H- Hz, 1H), 4.52 (t, J = 9.4 Hz, 1H), 4.46 (bs,[1,2,4]triazolo 1H), 4.35 (bs, 2H), 4.21 (dd, J = 9.5, 3.7 Hz,[4',3':1,6]pyrido]3,2- 1H), 4.02 (t, J = 10.8 Hz, 1H), 3.80 (t, J =b]benzofuro[4,3- 11.4 Hz, 1H), 3.02 (s, 3H) (rotamers); m/zfg][1,4]oxazonine- (ES+) [M]+: 451.21; LC-MS (A05) tR = 4-carboxamide2.03 min.

Example 56:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate Step 1: tributyl-(1-methylpyrazol-3-yl)stannane

n-BuLi in THF (0.960 mL, 2.40 mmol, 2.50 M) was added dropwise to asolution of 5-bromo-1-methyl-1H-pyrazole (0.322 g, 2.00 mmol) in THF(10.0 mL) at −78° C. The mixture was stirred at −78° C. for 30 min.Tributyltin chloride (0.651 mL, 2.40 mmol) was added dropwise. Themixture was stirred at −78° C. for 1 h, warmed to room temperature, andstirred for 2 h. Sat. NH₄Cl (10 mL) was added, and the aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic phases were washedwith brine (20 mL), dried over MgSO4, filtered, and concentrated. Theresidue was purified by silica gel chromatography (40 g cartridge)eluting with hexanes and EtOAc (0-20%) to provide the title compound asan oil (0.142 g, 19%). 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J=2.0 Hz, 1H),6.32 (d, J=2.1 Hz, 1H), 3.96 (s, 3H), 1.60-1.52 (m, 6H), 1.38-1.28 (m,6H), 1.10-1.04 (m, 6H), 0.88 (t, J=7.3 Hz, 9H); m/z (ES+) [M]+: 371.06(multiple Sn isotopes), HPLC tR (A05)=3.03 min.

Step 2: tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A solution of tributyl-(l-methylpyrazol-3-yl) stannane (51.0 mg, 0.137mmol) in toluene (1.50 mL) was added to a mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 50.0 mg, 0.102 mmol) and Pd(PPh3)4 (23.5 mg, 0.0204 mmol)under nitrogen. The mixture was heated at 110° C. for 20 h. The mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel chromatography (4 g cartridge) eluting with MeOH in DCM(0-15%) to provide tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (37.0 mg, 74%). m/z (ES+) [M+H]+: 493.49; HPLC tR (A05)=2.21min.

Step 3:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(37.0 mg, 75.1 μmol) in HFIP (2.00 mL) was heated at 100° C. for 16 h.The mixture was concentrated under reduced pressure, and the residue waspurified by HPLC (Gemini C18 30×100 mm AmBicarb/ACN 27-47%) to affordthe deprotected material as a solid (20.8 mg, 71%). 1H NMR (500 MHz,DMSO) δ 9.41 (s, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.73 (s, 1H), 7.44 (t,J=5.3 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 6.99-6.88 (m, 1H), 6.66 (dd,J=8.6, 3.8 Hz, 1H), 4.88 (d, J=11.4 Hz, 1H), 4.76 (d, J=11.6 Hz, 1H),4.55-4.50 (m, 2H), 4.24 (dd, J=9.6, 3.4 Hz, 1H), 4.06-3.97 (m, 1H), 3.90(s, 3H), 3.84 (t, J=11.5 Hz, 1H). m/z (ES+) [M+H]+: 392.38; HPLC tR(A05)=1.97 min.

Step 4:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate salt

Methanesulfonic acid (1.90 μL, 29.3 μmol) was added to a suspension of(S)-12-fluoro-4-(l-methyl-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(11.5 mg, 29.3 μmol) in MeCN (1.50 mL). The mixture was stirred at roomtemperature for 1 h. The mixture was concentrated under reduced pressureto provide the title compound as a solid (13.5 mg, 94%). 1H NMR (400MHz, CD3OD) δ 9.47 (s, 1H), 8.28 (s, 1H), 7.70 (d, J=2.4 Hz, 1H), 6.89(dd, J=10.3, 8.7 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.66 (dd, J=8.7, 3.9Hz, 1H), 5.14 (d, J=14.8 Hz, 1H), 4.94 (d, J=14.9 Hz, 1H), 4.76 (dd,J=9.9, 4.1 Hz, 1H), 4.60 (t, J=9.3 Hz, 1H), 4.31 (dd, J=9.7, 3.3 Hz,1H), 4.09-4.02 (m, 1H), 4.01 (s, 3H), 4.01-3.92 (m, 1H), 2.70 (s, 3H).m/z (ES+) [M-MeSO3H]+: 392.1; HPLC tR (B05)=1.53 min.

Example 57: General Procedure B. Preparation of(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq) in dioxane (5 mL) was added2-bromo-3,5-difluoro-pyridine (55.3 mg, 285 umol, 1.00 eq), CuI (21.7mg, 114 umol, 0.400 eq), Pd(PPh₃)₄ (33.0 mg, 28.5 umol, 0.100 eq) andLiCl (24.2 mg, 570 umol). Reaction completion was monitored by LC-MS.The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=1/4). tert-butyl(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, crude) was obtained as a yellow solid.

Step 2:(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 228 umol, 1.00 eq) in DCM (3 mL) was added TFA (1.5 mL) at 15°C. The mixture was stirred at 15° C. for 2 h. Reaction completion wasmonitored by LC-MS. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-HPLC (FA system).(S)-4-(3,5-difluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(50 mg, 104.59 umol, 45% yield, 98.607% purity, formate salt) wasobtained as a yellow solid. 1H NMR ET20970-310-P1C11 DMSO-d6 400 MHzδ=ppm 9.46 (s, 1H), 8.62 (s, 1H), 8.08 (br t, J=9.2 Hz, 1H), 7.75 (br t,J=5.6 Hz, 1H), 7.54 (s, 1H), 6.97 (t, J=9.6 Hz, 1H), 6.70 (dd, J=8.8,3.6 Hz, 1H), 4.98-4.88 (m, 1H), 4.87-4.76 (m, 1H), 4.60-4.46 (m, 2H),4.22 (br dd, J=9.4, 3.2 Hz, 1H), 4.05 (br s, 1H), 3.92-3.79 (m, 1H).LCMS (ESI+): m/z 426.1 (M+H).

Compounds 83, 93, 95, 101, 123, 135, 144, and 149 were preparedaccording to General Procedure B using the suitable starting materials,precursors, intermediates, and reagents.

Cmpd No. Compound Name Structure Spectral Data 95 (S)-12-fluoro-4-(3-

1H NMR DMSO-d6 400 MHz δ = ppm methyl pyridin-2-yl)- 9.48 (br s, 1H),8.49 (br s, 1H), 7.80 (br s, 7a,8,13,14-tetrahydro- 1H), 7.71 (br s,1H), 7.48 (s, 1H), 7.41 (br 7H-[1,2,4]triazolo s, 1H), 7.07−6.91 (m,1H), 6.71 (dd, J = [4',3':1,6]pyrido[3,2- 8.7, 3.8 Hz, 1H), 4.98−4.88(m, 1H), 4.88− b]benzofuro [4,3- 4.75 (m, 1H), 4.60−4.47 (m, 2H), 4.24fg][1,4] oxanzonine (dd, J = 9.6, 3.5 Hz, 1H), 4.05 (br s, 1H),3.91−3.79 (m, 1H), 2.24 (s. 3H). LCMS (ESI+): m/z 404.1 (M+H). 101(S)-4-(5-chloropyridin

1H NMR CD₃OD 400 MHz. δ = ppm 9.50 -2-yl)-12-fluoro-7a,8, (br s, 1H),8.71 (br s, 1H), 8.60 (s, 1H), 13,14-tetrahydro-7H- 8.17 (br s, 1H),7.99 (s, 1H), 6.90 (t, J = [1,2,4]triazolo 9.6 Hz, 1H), 6.66 (dd, J =8.6, 3.7 Hz, 1H), [4',3':1,6]pyrido]3,2- 5.19 (d, J = 14.8 Hz, 1H), 4.97(br d, J = b]benzofuro[4,3- 15.0 Hz, 1H), 4.79 (br d, J = 6.2 Hz, 1H),fg][1,4]oxazonine 4.62 (t, J = 9.2 Hz, 1H), 4.32 (dd, J = 9.5, 2.9 Hz,1H), 4.13−3.92 (m, 2H). LCMS (ESI+): m/z 424.0 (M+H). 144 (S)-4-(3-

¹H NMR DMSO-d₆ 400 MHz δ = ppm (difluoromethyl)-6- 9.43 (s, 1H), 8.01(d, J = 8.2 Hz, 1H), 7.67 methylpyridin-2-yl)- (br t, J = 6.3 Hz, 1H),7.44 (d, J = 8.2 Hz, 12-fluoro-7a,8,13,14- 1H), 7.41 (s, 1H), 7.05 (t, J= 52.8 Hz, tetrahydro-7H- 1H), 6.99−6.90 (m, 1H), 6.68 (dd, J = 8.6,[1,2,4]triazolo[4',3':1, 3.7 Hz, 1H), 4.96−4.87 (m, 1H), 4.83−6]pyrido]3,2- 4.74 (m, 1H), 4.56−4.46 (m, 2H), 4.22 b]benzofuro[4,3-(dd. J = 9.7, 3.5 Hz, 1H), 4.08−3.98 (m, fg][1,4]oxazonine 1H),3.86−3.80 (m, 1H), 2.54 (s, 3H). LCMS (ESI+): m/z 454.1 (M+H). 83(S)-12-fluoro-4-(2-

¹H NMR DMSO-d₆ 400 MHz δ = ppm (trifluoromethoxy) 9.40 (br d, J = 1.2Hz, 1H), 8.36 (dd, J = pyridin-3-yl)-7a, 5.2, 3.2 Hz, 2H), 7.68 (br t, J= 6.2 Hz, 8,13,14-tetrahydro- 1H), 7.58−7.48 (m, 2H), 6.96 (t, J = 9.57H-[1,2,4]triazolo Hz, 1H), 6.70 (dd, J = 8.6, 3.7 Hz, 1H),[4',3':1,6]pyrido]3,2- 4.90 (br d, J = 5.6 Hz, 1H), 4.81 (br s, 1H),b]benzofuro[4,3- 4.61−4.41 (m, 2H), 4.24−4.15 (m, 1H), fg][1,4]oxazonine4.04 (br s, 1H), 3.87 (br d, J = 11.5 Hz, 1H). LCMS (ESI+): m/z 474.2(M+H). 93 (S)-12-fluoro-4-

¹H NMR DMSO-d₆ 400 MHz δ = ppm (thiazol-5-yl)- 9.49 (s, 1H), 9.08 (s,1H), 8.70 (s, 1H), 7a,8,13,14- 7.87 (s, 1H), 7.75 (br t, J = 6.4 Hz,1H), tetrahydro-7H- 6.95 (dd, J = 10.1, 8.8 Hz, 1H), 6.68 (dd, J =[1,2,4]triazolo 8.7, 3.9 Hz, 1H), 4.95−4.86 (m, 1H),[4',3':1,6]pyrido]3,2- 4.85−4.76 (m, 1H), 4.59−4.47 (m, 2H),b]benzofuro[4,3-fg] 4.22 (dd, J = 9.6, 3.4 Hz, 1H), 4.09-3.99[1,4]oxazonine (m, 1H), 3.97−3.87 (m, 1H). LCMS (ESI+): m/z 396.1 (M+H).135 (S)-4-(1,4-dimethyl-

¹H NMR CD₃OD 400 MHz δ = ppm 9.54 1H-imidazol-2-yl)-12- (s, 1H), 8.04(s, 1H), 7.45 (s, 1H), 6.95− fluoro-7a,8,13,14- 6.87 (m, 1H), 6.68 (dd,J = 8.7, 3.9 Hz, tetrahydro-7H- 1H), 5.20 (d, J = 14.8 Hz, 1H), 4.96 (brd, [1,2,4]triazolo[4',3':1, J = 14.7 Hz, 1H), 4.74 (br d, J = 6.2 Hz,6]pyrido]3,2- 1H), 4.62 (t, J = 9.4 Hz, 1H), 4.31 (dd, J =b]benzofuro[4,3- 9.7, 3.2 Hz, 1H), 4.06 (br d, J = 2.8 Hz,fg][1,4]oxazonine 1H), 3.93 (br d, J = 10.9 Hz, 1H), 3.83 (s, 3H), 2.42(s, 3H). LCMS (ESI+): m/z 407.2 (M+H). 149 (S)-12-fluoro-4-(4-

¹H NMR CD₃OD 400 MHz δ = ppm 9.86 methylpyridin-2-yl)- (br s, 1H), 8.65(br s, 2H), 8.34 (br s, 1H), 7a,8,13,14- 7.61 (br s, 1H), 6.90 (br t, J= 9.3 Hz, 1H), tetrahydro-7H- 6.71−6.61 (m, 1H), 5.28−5.08 (m, 1H),[1,2,4]triazolo 5.04−4.96 (m, 1H), 4.81 (br s, 1H), 4.62[4',3':1,6]pyrido]3,2- (br t, J = 7.8 Hz, 1H), 4.32 (br d, J = 8.9b]benzofuro[4,3- Hz, 1H), 4.03 (br s, 2H), 2.67 (s, 3H).fg][1,4]oxazonine VTNMR DMSO-d₆ 400 MHz δ = ppm 8.81 (br s, 1H), 8.63(br s, 1H), 7.02−6.88 (m, 1H), 6.70 (br dd, J = 8.3, 3.3 Hz, 1H),5.07−4.87 (m, 2H), 4.66−4.51 (m, 2H), 4.25−4.18 (m, 1H), 4.15−4.06 (m,1H), 4.02 (br d, J = 10.8 Hz, 1H), 2.54 (s, 3H). LCMS (ESI+): m/z 404.1(M+H). 123 (S)-12-fluoro-4-(6-

1H NMR DMSO-d6 400 MHz δ = ppm methylpyridazin-4- 9.92 (d, J = 1.8 Hz,1H), 9.50 (s, 1H), 8.47 yl)-7a,8,13,14- (d, J = 2.0 Hz, 1H), 8.18 (s,1H), 8.06− tetrahydro-7H- 7.96 (m, 1H), 6.99−6.90 (m, 1H), 6.68[1,2,4]triazolo (dd, J = 8.7, 3.9 Hz, 1H), 4.97−4.89 (m,[4',3':1,6]pyrido[3,2- 1H), 4.84 (br s, 1H), 4.53 (br t, J = 9.3 Hz,b]benzofuro [4,3- 2H), 4.20 (dd, J = 9.3, 3.3 Hz, 1H), 4.04 fg][1,4]oxanzonine (br s, 1H), 3.99-−3.88 (m, 1H), 2.65 (s, 3H). LCMS (ESI+):m/z 405.1 (M+H)

Example 58:(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-iodo-5-methylpyrimidine

A mixture of 2-chloro-5-methylpyrimidine (1.00 g, 7.78 mmol, 1.00 eq) inHI (13.6 g, 50.0 mmol, 8.00 mL, 47% purity, 6.42 eq) was stirred at 0°C. for 1 hr under nitrogen atmosphere. LC-MS showed some of the startingmaterial remained. The mixture was stirred at 15° C. for additional 2 h.The reaction mixture was adjusted pH to 8-9 by added sat. aq. NaHCO₃ andextracted with EtOAc (50 mL*3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Then the residue was purified by flash silica gel (PE/MTBE=1/1) to give2-iodo-5-methylpyrimidine (400 mg, crude) as a white solid.

Step 2: tert-butyl(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 214 umol, 1.00 eq) in dioxane (4 mL) was added CuI (16.3 mg,85.5 umol, 0.400 eq), 2-iodo-5-methylpyrimidine (56.5 mg, 257 umol, 1.20eq), Pd(PPh3)4 (24.7 mg, 21.4 umol, 0.100 eq) and LiCl (18.1 mg, 428umol, 8.76 uL, 2.00 eq) at 15° C. The mixture was stirred at 80° C. for12 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,Petroleum ether/Ethyl acetate=0/1).(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(55.0 mg, crude) was obtained as yellow solid.

Step 3:(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninehydrochloride

To a solution of tert-butyl(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(55.0 mg, 109 umol, 1.00 eq) in DCM (2 mL) was added TFA (1.54 g, 13.5mmol, 1.00 mL, 124 eq) at 15° C. The mixture was stirred at 15° C. for 2h The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Welch Xtimate C18 150*40mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-50%, 12 min).(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(29.5 mg, 46.1 umol, 42% yield, 99.1% purity, formate salt) was obtainedas a yellow solid. The compound was additionally purified by prep-HPLC(column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 15%-50%, 10 min).(S)-12-fluoro-4-(5-methylpyrimidin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.0 mg, 56.5 umol, 51% yield, 99.6% purity, HCl salt) was obtained asa yellow solid. 1H NMR CD3OD 400 MHz δ=ppm 9.55 (s, 1H), 8.88 (s, 1H),8.79 (s, 2H), 6.93 (t, J=9.4 Hz, 1H), 6.69 (dd, J=8.5, 3.7 Hz, 1H), 5.24(br d, J=14.8 Hz, 1H), 5.01 (br d, J=15.6 Hz, 1H), 4.85-4.80 (m, 1H),4.70-4.61 (m, 1H), 4.35 (br d, J=6.8 Hz, 1H), 4.09 (br s, 1H), 4.04-3.94(m, 1H), 2.41 (s, 3H). LCMS (ESI+): m/z 405.2 (M+H).

Example 59:(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3,5-dimethylpyrazin-2-yl trifluoromethanesulfonate

To a solution of 3,5-dimethylpyrazin-2-ol (200 mg, 1.61 mmol, 1.00 eq)and TEA (326 mg, 3.22 mmol, 448 uL, 2.00 eq) in DCM (5 mL) was addedTf₂O (682 mg, 2.42 mmol, 399 uL, 1.50 eq) at 0° C. under nitrogenatmosphere. The mixture was stirred at 0° C. for 0.5 hr and then at 25°C. for 12 h. LC-MS showed 3,5-dimethylpyrazin-2-ol was consumedcompletely and one main peak with desired mass was detected. Thereaction mixture was quenched by addition of ice water (5 mL), and thendiluted with DCM (5 mL) and extracted with DCM (5 mL*3). The combinedorganic layers were washed with sat. aq. NaCl (10 mL), dried overNa2SO4, filtered and blown to dryness by nitrogen stream. The residuewas purified by prep-TLC (SiO₂, Petroleum ether:Ethyl acetate=3:1,R_(f)=0.5). 3,5-dimethylpyrazin-2-yl trifluoromethanesulfonate (200 mg,781 umol, 48% yield) was obtained as a yellow oil.

Step 2: tert-butyl(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq), 3,5-dimethylpyrazin-2-yltrifluoromethanesulfonate (110 mg, 428 umol, 1.50 eq), LiCl (36.3 mg,855 umol, 17.5 uL, 3.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq) indioxane (5 mL) was degassed and purged with nitrogen for 3 times at 25°C., and then the mixture was stirred at 100° C. for 17 h under nitrogenatmosphere. LC-MS showed presence of the starting material. The mixturewas stirred at 100° C. for 7 h The reaction was still incomplete byLC-MS. To the mixture was added 3,5-dimethylpyrazin-2-yltrifluoromethanesulfonate (110 mg, 428 umol, 1.500 eq), LiCl (36.3 mg,855 umol, 17.5 uL, 3.00 eq), Pd(PPh3)4 (33.0 mg, 28.5 umol, 0.100 eq) at25° C. under nitrogen atmosphere. The mixture was stirred at 100° C. for16 h. The reaction mixture was quenched by addition of water (5 mL), andthen diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL*3). Thecombined organic layers were washed with sat. aq. NaCl (10 mL), driedover Na2SO4, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Ethyl acetate:Methanol=10:1,R_(f)=0.5). tert-butyl(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(130 mg, 251 umol, 87% yield) was obtained as a yellow oil.

Step 3:(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

A mixture of tert-butyl(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 231.42 umol, 1.00 eq) in HFIP (5 mL) was degassed by purgingwith nitrogen 3 times at 25° C., and then the mixture was stirred at 80°C. for 12 h under nitrogen atmosphere. The mixture was concentrated invacuum. The residue was purified by prep-HPLC (formic acid conditions:column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 10%-40%, 12 min).(S)-4-(3,5-dimethylpyrazin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(24.5 mg, 52.2 umol, 22% yield, 99.0% purity, formate) was obtained as ayellow solid. 1H NMR CDCl3 400 MHz δ=ppm 9.02 (s, 1H), 8.33 (s, 1H),7.33 (s, 1H), 6.83 (t, J=9.4 Hz, 1H), 6.64 (dd, J=8.6, 3.9 Hz, 1H), 5.67(br s, 1H), 5.06 (br dd, J=14.5, 7.0 Hz, 1H), 4.84 (br dd, J=14.6, 6.1Hz, 1H), 4.65-4.54 (m, 2H), 4.22 (br d, J=7.8 Hz, 1H), 3.97-3.86 (m,2H), 2.58 (s, 3H), 2.53 (s, 3H). LCMS (ESI+): m/z 419.2 (M+H)

Example 60:(S)-12-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Pd(PPh3)4 (25.9 mg, 0.0224 mmol) was added to a mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 55.0 mg, 0.112 mmol),l-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (50.2 mg, 0.179 mmol), and NaHCO3 (47.0 mg, 0.560 mmol) in1,4-dioxane (1.00 mL) and water (0.200 mL). Nitrogen was bubbled throughthe mixture for 5 minutes. The mixture was stirred at 110° C. for 3 h.The mixture was cooled to room temperature and concentrated underreduced pressure. The residue was purified by silica gel chromatography(40 g cartridge) eluting with MeOH in DCM (0-10%) to provide tert-butyl(S)-12-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (56.0 mg, 87%). 1H NMR (400 MHz, cdcl3) (rotamers, partialcharacterization) δ 8.66 (s, 1H), 6.77 (s, 1H), 6.56 (s, 2H), 4.18 (t,J=5.6 Hz, 2H), 3.75 (t, J=5.6 Hz, 2H), 3.33 (s, 3H), 2.18 (s, 3H), 2.13(s, 3H), 1.36 (s, 9H). m/z (ES+) [M+H]+: 565.5. HPLC t_(R) (A05)=2.18min.

Step 2:(S)-12-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-12-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(56.0 mg, 99.2 μmol) in HFIP (2.00 mL) was heated at 100° C. for 5 h.The mixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (24 g cartridge) eluting with MeOHin DCM (0-10%) to afford the title compound 4 as a solid (37.0 mg, 80%).1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 6.94 (s, 1H), 6.84 (dd, J=10.1,8.8 Hz, 1H), 6.64 (dd, J=8.7, 3.9 Hz, 1H), 5.35 (s, 1H), 5.05 (dd,J=14.7, 7.0 Hz, 1H), 4.81 (dd, J=14.8, 5.8 Hz, 1H), 4.61 (t, J=9.4 Hz,1H), 4.53 (dd, J=10.0, 4.3 Hz, 1H), 4.22 (dd, J=9.7, 3.2 Hz, 1H), 4.17(t, J=5.7 Hz, 2H), 3.93 (dt, J=8.3, 6.2 Hz, 1H), 3.81 (dd, J=11.9, 10.1Hz, 1H), 3.75 (t, J=5.7 Hz, 2H), 3.32 (s, 3H), 2.21 (s, 3H), 2.18 (s,3H). m/z (ES+) [M+H]+: 466.1. HPLC t_(R) (A05)=2.03 min.

Example 61:(S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Toluene (2.00 mL) and dioxane (0.400 mL) were added to a mixture ofPd2(dba)3 (5.85 mg, 10.2 μmol) anddi-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.79 mg, 20.4 μmol) in a sealed tube. Nitrogen wasbubbled through the mixture. The mixture was heated at 120° C. for 4 minand added to a mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 100 mg, 204 μmol), 4-methyl-1H-pyrazole (25.3 μL, 305μmol), and K3P04 (86.4 mg, 407 μmol) under N2. The mixture was stirredat 120° C. for 7 h. The mixture was concentrated under reduced pressure,and the residue was purified by silica gel chromatography (40 gcartridge) eluting with MeOH in DCM (0-10%) to afford tert-butyl(S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (56.0 mg, 56%). m/z (ES+) [M+H]+: 493.8, HPLC tR (A05)=2.39min.

Step 2:(S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-12-fluoro-4-(4-methyl-1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(45.0 mg, 91.4 μmol) in HFIP (2.00 mL) was heated at 100° C. for 5 h.The mixture was concentrated under reduced pressure, and the residue waspurified by silica gel chromatography (24 g cartridge) eluting with MeOHin DCM (0-10%) to afford the title compound as a solid (26.0 mg, 73%).1H NMR (500 MHz, DMSO) δ 9.51 (s, 1H), 8.86 (s, 1H), 7.74 (s, 1H), 7.60(s, 1H), 7.44 (t, J=6.4 Hz, 1H), 6.94 (dd, J=10.3, 8.7 Hz, 1H), 6.67(dd, J=8.6, 3.8 Hz, 1H), 4.89-4.85 (m, 2H), 4.52 (t, J=9.4 Hz, 2H), 4.23(dd, J=9.6, 3.5 Hz, 1H), 4.07-3.99 (m, 1H), 3.87 (t, J=11.4 Hz, 1H),2.13 (s, 3H). m/z (ES+) [M+H]+: 393.1. HPLC tR (A05)=2.16 min.

Example 62:(S)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninehydrochloride

To a stirred solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(120 mg, 307 umol, 1.00 eq),1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(136 mg, 614 umol, 2.00 eq) and NaHCO3 (129 mg, 1.53 mmol, 5.00 eq) indioxane (4.00 mL) and water (0.800 mL) was added Pd(dppf)Cl2 (22.5 mg,30.7 umol, 0.100 eq) at 15° C. under N2. The resulting mixture wasstirred at 80° C. of 12 h. LCMS showed(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas remained and the desired mass was detected. The mixture was stirredat 80° C. for 6 h. LCMS showed(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineremained. To the mixture was added Pd(dppf)Cl2 (0.100 eq) at 15° C.under N2. The resulting mixture was stirred at 80° C. for 12 h. To themixture was added silica-thiol (400 mg, modified Silicon Gel forEliminating Pd, Irregular Silica Gel, 100-200 mesh, Chlorides (Cl),%≤0.004, Particle Size Distribution 45-75 um) at 15° C. and stirred at15° C. for 4 h. The suspension was filtered off and the filter cake waswashed with MeOH (5 mL*3). The filtrate was concentrated under reducedpressure. The residue was purified by acidic prep-HPLC (HCl conditions).The product-containing fraction was concentrated under reduced pressureto remove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(1,4-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.8 mg, 56.8 umol, 18% yield, 97.5% purity, HCl salt) was obtained asa yellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 10.19 (br s, 1H), 9.17 (brs, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.02 (br t, J=9.4 Hz, 1H), 6.75 (brdd, J=8.5, 3.4 Hz, 1H), 5.09-4.97 (m, 1H), 4.92 (br s, 1H), 4.62-4.49(m, 2H), 4.27-4.20 (m, 1H), 4.12 (br s, 1H), 3.91 (br s, 1H), 3.65 (s,3H), 1.90 (s, 3H). LCMS (ESI+): m/z 407.2 (M+H).

Example 63:(S)-4-(4-(difluoromethyl)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(150 mg, 383 umol, 1.00 eq) in EtOH (10.0 mL), water (2.00 mL) wereadded4-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(1.13 g, 4.39 mmol, 11.5 eq), Pd(Amphos)2Cl2 (27.2 mg, 38.3 umol, 0.100eq) and KOAc (75.3 mg, 767 umol, 2.00 eq) at 20° C. The mixture wasstirred at 80° C. for 2 h. LCMS indicated complete conversion. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was dissolved in MeOH (8.00 mL) and silica-thiol (600 mg,modified silicon gel for eliminating Pd, irregular silica gel, 100-200mesh, Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) wasadded at 20° C. and stirred at 20° C. for 12 h. The suspension wasfiltered and the filtrate was evaporated. The residue was purified byneutral prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um;mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 20%-50%, 8 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(4-(difluoromethyl)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(40.0 mg, 87.9 umol, 22% yield, 96.7% purity) was obtained as a yellowsolid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.48 (s, 1H), 9.38 (s, 1H), 9.15 (s,1H), 7.79 (br t, J=6.4 Hz, 1H), 7.51 (s, 1H), 7.06 (t, J=53.2 Hz, 1H),7.99 (t, J=10.0 Hz, 1H), 6.72 (dd, J=8.7, 3.8 Hz, 1H), 5.01-4.89 (m,1H), 4.87-4.72 (m, 1H), 4.61-4.46 (m, 2H), 4.23 (dd, J=9.6, 3.5 Hz, 1H),4.05 (br s, 1H), 3.96-3.86 (m, 1H). LCMS (ESI+): m/z 441.1 (M+H).

Example 64:(S)-4-(2-(difluoromethyl)-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(104 mg, 383 umol, 2.50 eq) in EtOH (4.00 mL) and water (0.560 mL) wasadded 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium(10.9 mg, 15.3 umol, 0.100 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(60.0 mg, 153 umol, 1.00 eq) and KOAc (45.2 mg, 460 umol, 3.00 eq) at20° C. under nitrogen atmosphere. The mixture was stirred at 80° C. for8 h under nitrogen atmosphere. LCMS showed the starting material wasconsumed completely and the desired MS was detected. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in MeOH (10.0 mL) and silica-thiol (100 mg, modified silicongel for eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides(Cl), %≤0.004, particle size distribution 45-75 um) was added at 20° C.and stirred at 20° C. for 4 h. The suspension was filtered and thefiltrate was concentrated and then purified by neutral prep-HPLC. Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(2-(difluoromethyl)-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(30.0 mg, 65.4 umol, 42% yield, 99.1% purity) was obtained as a yellowsolid. 1H NMR CDCl3 400 MHz δ=ppm 8.95 (s, 1H), 8.76 (s, 1H), 7.11 (s,1H), 6.91-6.84 (m, 1H), 6.68 (dd, J=8.8, 4.8 Hz, 1H), 6.67 (t, J=54.4Hz, 1H), 5.37 (t, J=6.8 Hz, 1H), 5.11 (dd, J=14.7, 7.4 Hz, 1H), 4.85(dd, J=14.4, 6.3 Hz, 1H), 4.70-4.57 (m, 2H), 4.26 (dd, J=9.7, 3.3 Hz,1H), 4.01-3.88 (m, 1H), 3.86-3.76 (m, 1H), 2.57 (s, 3H). LCMS (ESI+):m/z 455.1 (M+H).

Example 65:(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(220 mg, 448 umol, 1.00 eq),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (130 mg, 672umol, 1.50 eq) and Na2CO3 (94.9 mg, 896 umol, 2.00 eq) in dioxane (1.00mL) and water (0.100 mL) was added Pd(dppf)Cl2 (32.8 mg, 44.8 umol,0.100 eq) under nitrogen at 25° C. The resulting mixture was stirred at80° C. under nitrogen for 10 h. LCMS indicated incomplete conversion. Tothe mixture was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (130 mg, 672umol, 1.50 eq) and Pd(dppf)Cl2 (32.8 mg, 44.8 umol, 0.100 eq) at 25° C.The resulting mixture was stirred at 80° C. under nitrogen for 3 h. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, EtOAc:MeOH=5:1). tert-butyl(S)-12-fluoro-4-(1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(280 mg, crude) was obtained as yellow solid.

Step 2: tert-butyl(S)-12-fluoro-4-(I-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-12-fluoro-4-(1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 167 umol, 1.00 eq) and Cs2CO3 (109 mg, 334 umol, 2.00 eq) inDMF (2.00 mL) was stirred at 25° C. for 0.5 hr. 2,2,2-trifluoroethyltrifluoromethanesulfonate (58.2 mg, 251 umol, 1.50 eq) was added and themixture was stirred at 25° C. for 10 h The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=0:1). tert-butyl(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(65.0 mg, crude) was obtained as yellow oil.

Step 3:(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(85.0 mg, 152 umol, 1.00 eq) in DCM (1.50 mL) was added TFA (0.500 mL)at 15° C. The mixture was stirred at 15° C. for 10 h. The reactionmixture was concentrated under reduced pressure. The suspension wasfiltered and the filtrate was concentrated and then purified by acidicprep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase:[water (0.2% FA)-ACN]; B %: 20%-45%, 12 min).(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(22.7 mg, 43.8 umol, 28% yield, 97.7% purity, formate) was obtained as awhite solid. 1H NMR CD3OD 400 MHz δ=ppm 9.40 (s, 1H), 8.12 (s, 1H), 7.86(d, J=2.0 Hz, 1H), 7.15-7.10 (m, 1H), 6.91-6.83 (m, 1H), 6.67-6.60 (m,1H), 5.12-5.01 (m, 3H), 4.92 (s, 1H), 4.69 (br dd, J=9.9, 3.7 Hz, 1H),4.58 (t, J=9.2 Hz, 1H), 4.29 (dd, J=9.7, 3.2 Hz, 1H), 4.07-3.99 (m, 1H),3.99-3.90 (m, 1H). LCMS (ESI+): m/z 461.1 (M+H)

Example 66:(S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq) in EtOH (5.00 mL) and water (1.00 mL) wereadded4-(difluoromethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(690 mg, 2.56 mmol, 10.0 eq), KOAc (50.2 mg, 511 umol, 2.00 eq) and4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (18.1mg, 25.6 umol, 0.100 eq) at 25° C. under nitrogen atmosphere. Themixture was stirred at 80° C. for 2 h under nitrogen atmosphere. Thereaction mixture was filtered and the filtrate concentrated under highvacuum. The residue was dissolved in MeOH (5.00 mL) and silica-thiol(260 mg, modified silicon gel for eliminating Pd, irregular silica gel,100-200 mesh, Chlorides (Cl), %≤0.00400, particle size distribution45.0-75.0 um) was added at 25° C. and stirred at 25° C. for 3 h. Thesuspension was filtered and the filtrate was concentrated and purifiedby FA prep-HPLC (column: Phenomenex Luna C18 100*30.0 mm*5.00 um; mobilephase: [water (0.200% FA)-ACN]; B %: 20.0%-45.0%, 12.0 min). Thefraction containing the product was concentrated under reduced pressureto remove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(4-(difluoromethyl)-2-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(29.6 mg, 58.6 umol, 22% yield, 99.0% purity, formate) was obtained as ayellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.46 (s, 1H), 9.00 (s, 1H),7.73 (br t, J=6.2 Hz, 1H), 7.44 (s, 1H), 6.98 (t, J=9.6 Hz, 1H), 6.98(t, J=53.0 Hz 1H), 6.71 (dd, J=8.6, 3.7 Hz, 1H), 4.99-4.89 (m, 1H),4.86-4.75 (m, 1H), 4.59-4.52 (m, 1H), 4.49 (br d, J=6.1 Hz, 1H), 4.22(dd, J=9.6, 3.4 Hz, 1H), 4.10-3.98 (m, 1H), 3.95-3.83 (m, 1H), 2.76 (s,3H). LCMS (ESI+): m/z 455.1 (M+H)

Example 67:(S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-2-(difluoromethoxy)pyrimidine

To 5-bromopyrimidin-2-ol (5.00 g, 28.6 mmol, 1.00 eq),sodium;2-chloro-2,2-difluoro-acetate (8.71 g, 57.2 mmol, 2.00 eq), K₂CO₃(8.29 g, 60.0 mmol, 2.10 eq) was added in DMF (33.3 mL) at 20° C. Themixture was degassed and purged with nitrogen 3 times, and then themixture was stirred at 65° C. for 1.5 h under nitrogen atmosphere. LC-MSshowed 5-bromopyrimidin-2-ol was consumed completely and one main peakwith desired mass was detected. Water (150 mL) was added and the mixturewas extracted with EtOAc (150 mL*4). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 1/1).5-bromo-2-(difluoromethoxy)pyrimidine (191 mg, crude) was obtained asyellow oil. ¹H NMR CD₃OD 400 MHz δ=ppm 8.78 (s, 2H), 7.52 (t, J=71.6 Hz,1H)

Step 2:2-(difluoromethoxy)-5-(4,4,5f-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

To 5-bromo-2-(difluoromethoxy)pyrimidine (190 mg, 844 umol, 1.00 eq),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (429 mg,1.69 mmol, 2.00 eq), Pd(dppf)Cl₂.DCM (69.0 mg, 84.5 umol, 0.100 eq),KOAc (166 mg, 1.69 mmol, 2.00 eq) was added dioxane (3.00 mL) at 20° C.The mixture was degassed and purged with nitrogen 3 times, and then themixture was stirred at 80° C. for 4 h under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure to give2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(200 mg, crude) as brown solid.

Step 3:(S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(180 mg, 460 umol, 1.00 eq),2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(200 mg, 736 umol, 1.60 eq), Na₂CO₃ (97.5 mg, 920 umol, 2.00 eq),Pd(dppf)Cl₂ (33.7 mg, 46.0 umol, 0.100 eq) was added dioxane (3.00 mL)and water (0.300 mL) at 20° C. The mixture was degassed and purged withnitrogen 3 times, and then the mixture was stirred at 80° C. for 3 hunder nitrogen atmosphere. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in dioxane (10.0 mL) and silica-thiol (500 mg, modifiedsilicon gel for eliminating Pd, irregular silica gel, 100-200 mesh,Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) was addedat 20° C. and stirred at 20° C. for 3 h. The suspension was filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by acidic prep-HPLC (formic acid conditions). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(2-(difluoromethoxy)pyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(23.5 mg, 45.2 umol, 9% yield, 96.7% purity, formate) was obtained asyellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.49 (s, 2H), 9.46 (s, 1H),7.99 (s, 1H), 7.72 (t, J=71.6 Hz, 1H), 7.71 (br s, 1H), 6.95 (t, J=9.5Hz, 1H), 6.74-6.63 (m, 1H), 4.96-4.87 (m, 1H), 4.85-4.75 (m, 1H),4.60-4.48 (m, 2H), 4.27-4.17 (m, 1H), 4.09-3.99 (m, 1H), 3.98-3.88 (m,1H). LCMS (ESI+): m/z 457.1 (M+H).

Example 68:(S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(90.0 mg, 230 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL)was added (6-methoxy-4-methyl-3-pyridyl)boronic acid (76.8 mg, 460 umol,2.00 eq), Pd(dppf)Cl₂ (16.8 mg, 23.0 umol, 0.100 eq) and Na₂CO₃ (48.8mg, 460 umol, 2.00 eq) at 20° C. The mixture was stirred at 80° C. for 2h under nitrogen atmosphere. LCMS showed(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas consumed completely and the desired mass was detected. The reactionwas filtered, the filtrate was concentrated. The residue was dissolvedin MeOH (5.00 mL) and silica-thiol (600 mg, modified silicon gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 12 h. The suspension was filtered, the filtratewas concentrated and purified by acidic prep-HPLC (column: PhenomenexLuna C18 200*40 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:25%-45%, 12 min). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-12-fluoro-4-(6-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(65.0 mg, 136 umol, 58% yield, 100% purity, formate salt) was obtainedas a white solid. ¹H NMR DMSO-d₆ 400 MHz. δ=ppm 9.41 (s, 1H), 8.09 (s,1H), 7.48 (br t, J=6.2 Hz, 1H), 7.26 (s, 1H), 7.03-6.92 (m, 1H), 6.79(s, 1H), 6.75-6.66 (m, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.97-4.86 (m,1H), 4.82-4.74 (m, 1H), 4.58-4.40 (m, 2H), 4.22 (dd, J=9.5, 3.3 Hz, 1H),4.04 (br s, 1H), 3.87 (s, 3H), 3.83-3.80 (m, 1H), 2.15 (s, 3H). LCMS(ESI+): m/z 434.1 (M+H).

Example 69:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one

To a stirred solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq),l-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one(120 mg, 511 umol, 2.00 eq) and Na₂CO₃ (54.2 mg, 512 umol, 2.00 eq) indioxane (2.50 mL) and water (0.500 mL) was added Pd(dppf)Cl₂ (18.7 mg,25.6 umol, 0.100 eq) at 15° C. under N₂. The resulting mixture wasstirred at 80° C. for 3 h. The mixture was concentrated under reducedpressure. The mixture was purified by prep-TLC (SiO₂, EtOAc/MeOH=4/1) togive the crude product and the crude product was purified by acidicprep-HPLC (FA). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methylpyridin-2(1H)-one(18.8 mg, 39.6 umol, 15% yield, 98.1% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.44 (s, 1H), 8.82 (d,J=2.4 Hz, 1H), 8.23 (dd, J=9.6, 2.6 Hz, 1H), 7.60 (s, 1H), 7.45 (br t,7=6.1 Hz, 1H), 6.94 (dd, J=10.1, 9.0 Hz, 1H), 6.68 (dd, J=8.6, 3.9 Hz,1H), 6.50 (d, J=9.5 Hz, 1H), 4.92-4.83 (m, 1H), 4.81-4.72 (m, 1H),4.57-4.48 (m, 2H), 4.22 (dd, J=9.4, 3.1 Hz, 1H), 4.07-3.98 (m, 1H),3.97-3.88 (m, 1H), 3.53 (s, 3H). LCMS (ESI+): m/z 420.1 (M+H).

Example 70:(S)-12-fluoro-4-(2-(trifluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq) in dioxane (3.60 mL) and water (0.400 mL)were added [2-(trifluoromethyl)-3-pyridyl]boronic acid (195 mg, 1.02mmol, 4.00 eq), Na₂CO₃ (67.7 mg, 639 umol, 2.50 eq) and Pd(dppf)Cl₂(18.7 mg, 25.6 umol, 0.100 eq) at 25° C. under nitrogen atmosphere. Themixture was stirred at 80° C. for 12 h under nitrogen atmosphere. LC-MSshowed(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas remained and one main peak with desired mass was detected. To themixture were added [2-(trifluoromethyl)-3-pyridyl]boronic acid (97.6 mg,511 umol, 2.00 eq), Na₂CO₃ (67.7 mg, 639 umol, 2.50 eq) and Pd(dppf)Cl₂(18.7 mg, 25.7 umol, 0.100 eq) at 25° C. under nitrogen atmosphere. Themixture was stirred at 80° C. for 3 h under nitrogen atmosphere. Thereaction mixture (combined with another batch from 50 mg of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine)was filtered and the filtrate concentrated under high vacuum. Theresidue was dissolved in MeOH (5.00 mL) and silica-thiol (540 mg,modified silicon gel for eliminating Pd, irregular silica gel, 100-200mesh, Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) wasadded at 25° C. and stirred at 25° C. for 3 h. The suspension wasfiltered, the filtrate was concentrated and purified by prep-HPLC(column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 20.0%-50.0%, 12 min. The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-12-fluoro-4-(2-(trifluoromethyl)pyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(24.2 mg, 46.6 umol, 18% yield, 96.9% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.44 (s, 1H), 8.80 (brd, J=3.8 Hz, 1H), 8.09 (br d, J=7.5 Hz, 1H), 7.79 (dd, J=7.8, 4.7 Hz,1H), 7.62 (br s, 1H), 7.30 (s, 1H), 6.97 (t, 7=9.5 Hz, 1H), 6.71 (dd,J=8.6, 3.7 Hz, 1H), 4.99-4.86 (m, 1H), 4.83-4.69 (m, 1H), 4.59-4.40 (m,2H), 4.21 (br dd, J=9.6, 3.2 Hz, 1H), 4.02 (br s, 1H), 3.88-3.70 (m,1H). LCMS (ESI+): m/z 458.1 (M+H).

Example 71:(S)-12-fluoro-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Two parallel reactions were set up (each of 100 mg(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine).To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq),2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(127 mg, 511 umol, 2.00 eq) in water (0.400 mL), EtOH (4.00 mL) wasadded 4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium(36.2 mg, 51.1 umol, 0.200 eq), KOAc (75.3 mg, 767 umol, 3.00 eq) at 25°C., then the mixture was stirred at 80° C. for 12 h under N₂. Thebatches were combined. The resulting mixture was concentrated, theresidue was dissolved in MeOH (4.0 mL) and silica-thiol (40.0 mg,modified silicon gel for eliminating Pd, irregular silica gel, 100-200mesh, Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) wasadded at 20° C. and stirred at 20° C. for 2 h. The suspension wasfiltered, the filtrate was concentrated and purified by prep-HPLC(column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 30%-40%, 8 min). The fraction was thenblown to dryness by nitrogen stream to remove most of MeCN and theaqueous phase was lyophilized.(S)-12-fluoro-4-(2-methoxy-4-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.0 mg, 56.7 umol, 11% yield, 98.3% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.38 (s, 1H), 8.08-8.04 (m, 1H),7.46-7.35 (m, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.00-6.90 (m, 2H), 6.73-6.63(m, 1H), 4.94-4.85 (m, 1H), 4.80-4.68 (m, 1H), 4.57-4.48 (m, 1H), 4.43(br dd, J=10.0, 4.1 Hz, 1H), 4.24-4.15 (m, 1H), 4.07-3.96 (m, 1H), 3.72(br s, 1H), 3.65 (s, 1.5H), 3.71 (s, 1.5H), 2.03 (s, 1.5H), 1.92 (s,1.5H). LCMS (ESI+): m/z 434.2 (M+H).

Example 72:(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: (1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)boronic acid

To a solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g,10.3 mmol, 1.00 eq) in MeCN (50.0 mL) was added Cs₂CO₃ (6.72 g, 20.6mmol, 2.00 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.59g, 15.5 mmol, 1.50 eq) at 20° C. The mixture was stirred at 20° C. for 3h. LC-MS showed no5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wasremained. Several new peaks were shown on LC-MS and desired m/s wasdetected. The reaction mixture was filtered, and the filtrate wasdiluted with water (50.0 mL) and extracted with DCM (40.0 mL*3). Thecombined organic layers were washed with water (90.0 mL*4), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (column: Welch Xtimate C18 250*50 mm*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 0%-20%, 20 min).(l-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)boronic acid (200 mg, crude)was obtained as a yellow oil.(l-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)boronic acid (900 mg, crude)was obtained as a white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 7.93-7.84(m, 1H), 6.73-6.61 (m, 1H), 5.27-5.19 (m, 2H).

Step 2:(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(90.0 mg, 230 umol, 1.00 eq) in dioxane (5.00 mL) was addedPd(dppf)Cl₂.DCM (18.8 mg, 23.0 umol, 0.100 eq), Na₂CO₃ (73.2 mg, 690umol, 3.00 eq), (l-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)boronic acid(89.2 mg, 460 umol, 2.00 eq) and water (0.500 mL) at 20° C. under N₂.The mixture was stirred at 80° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in MeOH(3.00 mL) and silica-thiol (50.0 mg, modified silicon gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 2 h. The suspension was filtered, the filtrate wasconcentrated and purified by prep-HPLC (column: Phenomenex Luna C18100*30 mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B %: 35%-65%, 10min). The product-containing fraction was concentrated under reducedpressure to remove most of MeCN at 30° C. and the aqueous phase waslyophilized.(S)-12-fluoro-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(65.0 mg, 141 umol, 61% yield, 99.7% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.48 (s, 1H), 7.77 (br t, J=6.4 Hz,1H), 7.68 (d, J=1.6 Hz, 1H), 7.47 (s, 1H), 6.97 (dd, J=10.0, 8.8 Hz,1H), 6.71 (dd, J=8.7, 3.6 Hz, 1H), 6.61 (d, J=1.8 Hz, 1H), 5.37-5.24 (m,2H), 4.97-4.88 (m, 1H), 4.85-4.75 (m, 1H), 4.59-4.46 (m, 2H), 4.23 (dd,J=9.6, 3.6 Hz, 1H), 4.04 (br s, 1H), 3.93-3.81 (m, 1H). LCMS (ESI+): m/z461.1 (M+H).

Example 73:(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-fluoro-2-methyl-6-(trimethylstannyl)pyridine

To a solution of 6-bromo-3-fluoro-2-methylpyridine (1.00 g, 5.26 mmol,1.00 eq) in dioxane (20.0 mL) were addedtrimethyl(trimethylstannyl)stannane (3.44 g, 10.5 mmol, 2.18 mL, 2.00eq) and Pd(PPh₃)₄ (608 mg, 526 umol, 0.100 eq) at 20° C., the mixturewas stirred at 100° C. for 4 h under nitrogen atmosphere. The obtainedsolution of 3-fluoro-2-methyl-6-(trimethylstannyl)pyridine (1.44 g, 5.26mmol theoretical yield) in dioxane (20.0 mL) was used in the next stepdirectly.

Step 2: tert-butyl(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 3-fluoro-2-methyl-6-(trimethylstannyl)pyridine (2.85mmol, 7.00 eq. based on the theoretical yield in the previous step) indioxane were added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq), Pd(PPh₃)₄ (47.0 mg, 40.7 umol, 0.100 eq),CuI (31.0 mg, 163 umol, 0.400 eq) and LiCl (34.5 mg, 814 umol, 2.00 eq)at 20° C. The mixture was stirred at 80° C. for 12 h under nitrogenatmosphere. LC-MS showed tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and the desired mass was detected. The reactionmixture was filtered, the filtrate was concentrated. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/1).tert-butyl(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 288 umol, 70% yield) was obtained as a yellow oil.

Step 3: (S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 268 umol, 1.00 eq) in TFA (3.00 mL) and DCM (6.00 mL) wasstirred at 20° C. for 2 h. The reaction mixture was concentrated. Theresidue was dissolved in DMSO (4.00 mL). The solution was purified byacidic prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobilephase: [water (0.2% FA)-ACN]; B %: 20%-50%, 12 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(33.0 mg, 70.3 umol, 26% yield, 99.6% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (br s, 1H), 8.77(br d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.73 (br s, 1H), 7.65 (t, 7=8.9 Hz,1H), 6.86 (br t, J=9.5 Hz, 1H), 6.58 (dd, J=8.6, 3.7 Hz, 1H), 4.87-4.68(m, 2H), 4.42 (br t, J=9.4 Hz, 2H), 4.20-4.10 (m, 1H), 3.95 (br s, 1H),3.85-3.74 (m, 1H), 2.44 (s, 3H). LCMS (ESI+): m/z 422.1 (M+H).

Example 74:(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Pd(OAc)₂ (34.3 mg, 0.153 mmol) and di(l-adamantyl)-n-butylphosphinehydroiodide (149 mg, 0.305 mmol) were added to a solution of3,4-dimethyl-1,2,4-triazole (74.1 mg, 0.763 mmol), (Example 16; 150.0mg, 0.305 mmol), 2,2-dimethylpropanoic acid (31.2 mg, 0.305 mmol), andK2CO3 (127 mg, 0.916 mmol) in toluene (2.50 mL). The mixture was stirredat 120° C. for 6 h. Water (0.5 mL) was added. The mixture was extractedwith ethyl acetate (3×25 mL). The combined organic layers were driedover Na2SO4, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (4 g cartridge)eluting with MeOH in DCM (0-10%) to provide tert-butyl(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (66.0 mg, 30%, 70% purity). 1H NMR (400 MHz, MeOD) δ 9.19(br, 1H), 7.73 (s, 1H), 6.74-6.62 (m, 1H), 6.59 (dd, J=8.5, 3.7 Hz, 1H),5.35-5.20 (m, 1H), 4.72-4.63 (m, 1H), 4.47 (dd, J=9.6, 7.7 Hz, 1H), 4.34(d, J=9.6 Hz, 1H), 4.18-4.08 (m, 1H), 4.08-4.01 (m, 2H), 3.77 (s, 3H),2.37 (s, 3H), 1.56-1.33 (m, 9H). m/z (ES+) [M+H]+: 508.6; HPLC t_(R)(A05)=2.01 min.

Step 2:(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(66.0 mg, 70% pure, 91.0 μmol) in HFIP (2.50 mL) was heated at 100° C.for 15 h. After evaporating the solvent under reduced pressure, theresidue was purified by HPLC (Gemini C18 30×100 mm AmBicarb/ACN 23-43%)to afford the title compound as a solid (16.3 mg, 44%). ¹H NMR (500 MHz,DMSO) δ 9.48-9.39 (s, 1H), 7.83 (t, J=5.4 Hz, 1H), 7.54 (s, 1H),7.02-6.91 (m, 1H), 6.70 (dd, J=8.6, 3.8 Hz, 1H), 4.93 (dd, J=15.0, 6.1Hz, 1H), 4.85-4.75 (m, 1H), 4.54 (t, J=9.5 Hz, 1H), 4.51-4.41 (m, 1H),4.22 (dd, J=9.6, 3.6 Hz, 1H), 4.05 (s, 1H), 3.91-3.78 (m, 1H), 3.49 (s,3H), 2.42 (s, 3H). m/z (ES+) [M+H]⁺: 408.6; HPLC t_(R) (A05)=1.80 min.

Example 75:(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Pd(OAc)₂ (36.3 mg, 0.162 mmol) and di(l-adamantyl)-n-butylphosphinehydroiodide (157 mg, 0.324 mmol) were added to a solution of2-methyl-1,3,4-oxadiazole (68.0 mg, 0.809 mmol) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 16; 159 mg, 0.324 mmol), 2,2-dimethylpropanoic acid (33.1 mg,0.324 mmol), K₂CO₃ (134 mg, 0.971 mmol) in toluene (2.50 mL). Themixture was stirred at 120° C. for 6 h. Water (0.5 mL) was added. Theaqueous phase was extracted with ethyl acetate (3×15 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatography(4 g cartridge) eluting with MeOH in DCM (0-10%) to provide tert-butyl(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (99.0 mg, 43%, 70% purity), m/z (ES+) [M+H]⁺: 495.4; (A05)t_(R)=2.09 min.

Step 2:(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-12-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(99.0 mg, 70% pure, 140 μmol) in HFIP (2.50 mL) was heated at 100° C.for 15 h. After evaporating the solvent under reduced pressure, theresidue was purified by HPLC (BEH C18 30×150 mm ACN/AmBic 25-45%) toafford the title compound as a solid (18.6 mg, 34%). ¹H NMR (500 MHz,DMSO) δ 9.51 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.03-6.90 (m, 1H),6.70 (dd, J=8.7, 3.8 Hz, 1H), 4.99-4.90 (m, 1H), 4.90-4.81 (m, 1H), 4.53(t, J=9.4 Hz, 2H), 4.26-4.15 (m, 1H), 4.09-4.00 (m, 1H), 3.94-3.83 (m,1H), 2.59 (s, 3H). m/z (ES+) [M+H]⁺: 395.5; HPLC t_(R) (A05)=1.88 min.

Example 76:(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-bromo-2-methyl-6-vinylpyridine

To a stirred solution of 3,6-dibromo-2-methylpyridine (8.60 g, 34.3mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5.28 g,34.3 mmol, 1.00 eq) and Na₂CO₃ (7.27 g, 68.6 mmol, 2.00 eq) in dioxane(90.0 mL) and water (18.0 mL) was added Pd(dppf)Cl₂ (2.51 g, 3.43 mmol,0.100 eq) at 15° C. under N₂. The resulting mixture was stirred at 80°C. for 12 h. The mixture was concentrated under reduced pressure. Themixture was purified by MPLC (SiO₂, PE/EtOAc=1/0 to 1/1).3-bromo-2-methyl-6-vinylpyridine (5.70 g, 28.8 mmol, 84% yield) wasobtained as colourless oil.

Step 2: 5-bromo-6-methylpicolinaldehyde

Ozone (15 psi) was bubbled into a solution of3-bromo-2-methyl-6-vinylpyridine (5.70 g, 28.8 mmol, 1.00 eq) in DCM(100 mL) at −78° C. for 0.5 hr. After excess O₃ was purged with O₂ for0.5 hr, to the mixture was added Me₂S (35.8 g, 576 mmol, 42.3 mL, 20.0eq) at −78° C. The resulting mixture was stirred at 15° C. for 12 h. Themixture was concentrated under reduced pressure. The mixture waspurified by MPLC (SiO₂, PE/EtOAc=1/0 to 10/1).5-bromo-6-methylpicolinaldehyde (1.60 g, 8.00 mmol, 27% yield) wasobtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.92 (s, 1H),8.27 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 2.68 (s, 3H).

Step 3: 3-bromo-6-(difluoromethyl)-2-methylpyridine

To a stirred solution of 5-bromo-6-methylpicolinaldehyde (1.60 g, 8.00mmol, 1.00 eq) in DCM (50.0 mL) was added DAST (2.84 g, 17.6 mmol, 2.32mL, 2.20 eq) at −78° C. under N₂. The resulting mixture was stirred at15° C. for 12 h. The mixture was basified by saturated aqueous NaHCO₃solution to pH=78 and then the mixture was extracted with EtOAc (20mL*3). The combined organic layers were dried over Na₂SO₄ and thenconcentrated under reduced pressure. The mixture was purified by MPLC(SiO₂, PE/EtOAc=1/0 to 1/1). 3-bromo-6-(difluoromethyl)-2-methylpyridine(1.40 g, 6.31 mmol, 78% yield) was obtained as colourless oil.

Step 4: 6-(difluoromethyl)-2-methyl-3-(tributylstannyl)pyridine

To a solution of 3-bromo-6-(difluoromethyl)-2-methylpyridine (1.30 g,5.86 mmol, 1.00 eq) in THF (15.0 mL) was added n-BuLi (2.50 M, 2.58 mL,1.10 eq) at −78° C. under nitrogen and the mixture was stirred at −78°C. for 0.5 hr under N₂. Then tributyl(chloro)stannane (5.72 g, 17.6mmol, 4.73 mL, 3.00 eq) was added to the mixture under nitrogenatmosphere at −78° C. and the resulting mixture was stirred at −78° C.for 2 h under N₂. The mixture was quenched with saturated aqueous NH₄Clsolution (20.0 mL) and the mixture was extracted with EtOAc (20.0 mL*3).The combined organic layers were dried over Na₂SO₄ and then concentratedunder reduced pressure. The mixture was purified by MPLC (SiO₂,PE/EtOAc=1/0 to 1/1).6-(difluoromethyl)-2-methyl-3-(tributylstannyl)pyridine (1.00 g, 2.31mmol, 39% yield) was obtained as yellow oil.

Step 5: tert-butyl(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(130 mg, 265 umol, 1.00 eq),6-(difluoromethyl)-2-methyl-3-(tributylstannyl)pyridine (263 mg, 609umol, 2.30 eq), CuI (20.2 mg, 106 umol, 0.400 eq) and LiCl (22.4 mg, 529umol, 2.00 eq) in dioxane (4.00 mL) was added Pd(PPh₃)₄ (30.6 mg, 26.5umol, 0.100 eq) at 15° C. under N₂. The resulting mixture was stirred at80° C. for 12 h. The mixture was concentrated under reduced pressure.The mixture was purified by prep-TLC (SiO₂, PE/EtOAc=0/1). tert-butyl(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, crude) was obtained as yellow oil.

Step 6:(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 361 umol, 1.00 eq) was added HFIP (3.00 mL) at 15° C. Theresulting mixture was stirred at 80° C. for 12 h. LCMS showed thereactant was consumed and the desired mass was detected. The mixture wasconcentrated under reduced pressure. The mixture was purified by neutralprep-HPLC. The fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(6-(difluoromethyl)-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(15.2 mg, 31.6 umol, 8% yield, 94.2% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (s, 1H), 7.97 (d, J=7.7 Hz,1H), 7.63-7.53 (m, 2H), 7.39 (s, 1H), 6.96 (t, J=54.8 Hz, 1H), 6.96 (t,J=10.6 Hz, 1H), 6.68 (dd, J=8.6, 3.7 Hz, 1H), 4.95-4.87 (m, 1H),4.84-4.73 (m, 1H), 4.57-4.41 (m, 2H), 4.19 (dd, J=9.7, 3.5 Hz, 1H),4.09-3.97 (m, 1H), 3.91-3.81 (m, 1H), 2.41 (s, 3H). LCMS (ESI+): m/z454.2 (M+H).

Example 77:(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 6-bromo-2-methylnicotinaldehyde

To a solution of 3,6-dibromo-2-methylpyridine (10.0 g, 39.9 mmol, 1.00eq) in Et₂O (230 mL) was added n-BuLi (2.50 M, 18.3 mL, 1.15 eq) at −78°C. and the reaction mixture was stirred at −78° C. for 1 hr. TLC (SiO₂,PE/EtOAc=10/1) showed 3,6-dibromo-2-methylpyridine was consumedcompletely and new spots were formed. To the mixture was added DMF (5.15g, 70.5 mmol, 5.42 mL, 1.77 eq) at −78° C. and the reaction mixture wasstirred at −78° C. for 1 hr. Then the mixture was stirred at 15° C. for1 hr. TLC (SiO₂, PE/EtOAc=10/1) showed the intermediate was consumedcompletely and new spots were formed. The mixture was quenched withsaturated aqueous NH₄Cl solution (80.0 mL) and the mixture was extractedwith EtOAc (50.0 mL*3). The combined organic layers were dried overNa₂SO₄ and then concentrated under reduced pressure. The mixture waspurified by MPLC (SiO₂, PE/EtOAc=1/0 to 1/1).6-bromo-2-methylnicotinaldehyde (5.20 g, 26.0 mmol, 65% yield) wasobtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 10.22 (s, 1H),8.05 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 2.75 (s, 3H).

Step 2: 6-bromo-3-(difluoromethyl)-2-methylpyridine

To a stirred solution of 6-bromo-2-methylnicotinaldehyde (2.00 g, 10.0mmol, 1.00 eq) in DCM (80.0 mL) was added DAST (3.55 g, 22.0 mmol, 2.91mL, 2.20 eq) at −78° C. under N₂. The resulting mixture was stirred at15° C. for 12 h. LCMS showed 6-bromo-2-methylnicotinaldehyde wasconsumed and the desired mass was detected. The mixture was basified bysaturated aqueous NaHCO₃ solution to pH=7-8 and then the mixture wasextracted with EtOAc (50 mL*3). The combined organic layers were driedover Na₂SO₄ and then concentrated under reduced pressure. The mixturewas purified by MPLC (SiO₂, PE/EtOAc=1/0 to 1/1).6-bromo-3-(difluoromethyl)-2-methylpyridine (1.70 g, 7.66 mmol, 76%yield) was obtained as yellow oil.

Step 3: 3-(difluoromethyl)-2-methyl-6-(trimethylstannyl)pyridine

To a solution of 6-bromo-3-(difluoromethyl)-2-methylpyridine (500 mg,2.25 mmol, 1.00 eq) in dioxane (15.0 mL) was addedtrimethyl(trimethylstannyl)stannane (1.49 g, 4.50 mmol, 943 uL, 2.00eq), Pd(PPh₃)₄ (260 mg, 225 umol, 0.100 eq) at 25° C. under nitrogenatmosphere. The sealed tube was heated at 110° C. for 3 h undermicrowave irradiation. The suspension was filtered through a pad ofCelite gel and the filter cake was washed with dioxane (1.00 mL).3-(difluoromethyl)-2-methyl-6-(trimethylstannyl)pyridine (680 mg, 2.22mmol, 98% yield) was obtained as yellow oil (in 16.0 mL of dioxane).

Step 4: tert-butyl(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of3-(difluoromethyl)-2-methyl-6-(trimethylstannyl)pyridine (340 mg, 1.11mmol, 5.46 eq) in dioxane (8.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 204 umol, 1.00 eq), LiCl (17.3 mg, 407 umol, 8.34 uL, 2.00 eq),CuI (15.5 mg, 81.4 umol, 0.400 eq) and Pd(PPh3)4 (23.5 mg, 20.4 umol,0.100 eq) at 15° C. under nitrogen atmosphere. The mixture was stirredat 80° C. for 3 h. The mixture was concentrated under reduced pressure.The residue was purified by prep-TLC (SiO₂, PE/EtOAc=1/1). tert-butyl(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, crude) was obtained as a yellow oil.

Step 5:(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 271 umol, 1.00 eq) was added HFIP (4.00 mL) at 15° C. Theresulting mixture was stirred at 80° C. for 12 h. The mixture wasconcentrated under reduced pressure. The mixture was purified by neutralprep-HPLC. The fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(5-(difluoromethyl)-6-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(14.0 mg, 29.7 umol, 11% yield, 96.1% purity) was obtained as yellowsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.49 (s, 1H), 8.96 (d, J=8.4 Hz,1H), 8.35 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.90 (br s, 1H), 7.24 (t,J=54.8 Hz, 1H), 6.94 (t, J=9.5 Hz, 1H), 6.67 (dd, J=8.7, 3.6 Hz, 1H),4.98-4.75 (m, 2H), 4.50 (br t, J=9.4 Hz, 2H), 4.31-4.20 (m, 1H),4.10-3.99 (m, 1H), 3.95-3.82 (m, 1H), 2.63 (s, 3H). LCMS (ESI+): m/z454.2 (M+H).

Example 78:(S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-olStep 1: 4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol

To a solution of 3-bromo-2-iodopyridine (2.00 g, 7.04 mmol, 1.00 eq) inTHF (20.0 mL), Et₃N (20.0 mL) were added 2-methylbut-3-yn-2-ol (652 mg,7.75 mmol, 757 uL, 1.10 eq), Pd(PPh₃)₂C₁₋₂ (494 mg, 704 umol, 0.100 eq)and CuI (134 mg, 704 umol, 0.100 eq) at 20° C. The mixture was stirredat 70° C. for 12 h under nitrogen atmosphere. The reaction was filtered,the filtrate was concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1).4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (1.51 g, 6.29 mmol, 89%yield) was obtained as a yellow oil.

Step 2:3-bromo-2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridine

To a solution of 4-(3-bromopyridin-2-yl)-2-methylbut-3-yn-2-ol (600 mg,2.50 mmol, 1.00 eq), 2,6-dimethylpyridine (535 mg, 4.99 mmol, 582 uL,2.00 eq) in MeCN (10.0 mL) was added TBDMS-OTf (1.06 g, 4.00 mmol, 919uL, 1.60 eq) at 0° C. Then the mixture was stirred at 60° C. for 12 hunder nitrogen atmosphere. The reaction was concentrated. The residuewas purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=3/1).3-bromo-2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridine(800 mg, 2.26 mmol, 90% yield) was obtained as a yellow oil.

Step 3:2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(tributylstannyl)pyridine

To a solution of3-bromo-2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridine(1.00 g, 2.82 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M,1.24 mL, 1.10 eq) at −70° C. under nitrogen atmosphere. The reactionmixture was stirred at −70° C. for 0.5 hr under nitrogen atmosphere,then tributyl(chloro)stannane (2.76 g, 8.48 mmol, 2.28 mL, 3.00 eq) wasadded under nitrogen atmosphere and the resulting mixture was stirred at−70° C. for 2 h under nitrogen atmosphere. The reaction solution waspoured into water (10.0 mL), the mixture was extracted with ethylacetate (10 mL*3), the combined organic layers were dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Petroleum ether/Ethyl acetate=10/1).2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(tributylstannyl)pyridine(1.30 g, 2.30 mmol, 81% yield) was obtained as a yellow oil.

Step 4: tert-butyl(S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(240 mg, 488 umol, 1.00 eq) in dioxane (8.00 mL) was added2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)-3-(tributylstannyl)pyridine(551 mg, 976 umol, 2.00 eq), CuI (37.2 mg, 195 umol, 0.400 eq), LiCl(41.4 mg, 977 umol, 2.00 eq) and Pd(PPh₃)₄ (56.5 mg, 48.9 umol, 0.100eq) at 20° C. under nitrogen atmosphere. The mixture was stirred at 80°C. for 12 h under nitrogen atmosphere. The reaction was concentrated.The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=1/2). tert-butyl(S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(300 mg, 437 umol, 89% yield) was obtained as a yellow oil.

Step 5: tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(280 mg, 408 umol, 1.00 eq) in THF (8.00 mL) was added TBAF (1.00 M, 815uL, 2.00 eq) at 20° C. The mixture was stirred at 40° C. for 12 h. LCMSshowed tert-butyl(S)-4-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbut-1-yn-1-yl)pyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and the desired mass was detected. Water (10.0mL) was added to the reaction solution, the mixture was extracted withethyl acetate (10.0 mL*3), the combined organic layers were dried overNa₂SO₄, and concentrated under reduced pressure, tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(230 mg, crude) was obtained as a brown oil.

Step 6: tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 350 umol, 1.00 eq) in MeOH (15.0 mL) was added 10% Pd/C (80.0mg, 50% purity) at 20° C. under nitrogen atmosphere. The suspension wasdegassed and purged with H₂ three times. The mixture was stirred underH₂ (15 Psi) at 40° C. for 3 h. The reaction was filtered, the filtratewas concentrated. tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, crude) was obtained as a yellow oil.

Step 7:(S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-ol

A mixture of tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 347 umol, 1.00 eq) in HFIP (20.0 mL) was stirred at 80° C. for12 h. LCMS showed tert-butyl(S)-12-fluoro-4-(2-(3-hydroxy-3-methylbutyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateremained and the desired mass was detected. The mixture was stirred at100° C. for 3.5 h at which time LCMS showed complete conversion. Thereaction mixture was concentrated. The residue was dissolved in DMSO(8.00 mL). The solution was purified by neutral prep-HPLC. The fractioncontaining the product was concentrated under reduced pressure to removemost of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylbutan-2-ol(24.0 mg, 49.4 umol, 14% yield, 97.9% purity) was obtained as a whitesolid. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.77 (s, 1H), 8.47 (br d, J=3.4 Hz,1H), 7.61 (br d, J=7.8 Hz, 1H), 7.13 (dd, J=7.6, 5.0 Hz, 1H), 6.99 (s,1H), 6.81 (t, J=9.4 Hz, 1H), 6.60 (dd, J=8.6, 3.9 Hz, 1H), 5.08-4.91 (m,2H), 4.76 (br dd, J=14.1, 4.6 Hz, 1H), 4.59-4.47 (m, 2H), 4.17 (dd,J=9.8, 2.7 Hz, 1H), 3.91-3.63 (m, 3H), 2.79 (br t, J=7.2 Hz, 2H), 1.85(br t, J=7.4 Hz, 2H), 1.07 (s, 6H). LCMS (ESI+): m/z 476.0 (M+H).

Example 79:(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-4-(2,4-dioxopentan-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(250 mg, 509 umol, 1.00 eq), pentane-2,4-dione (509 mg, 5.09 mmol, 523uL, 10.0 eq) in toluene (5.00 mL) was added t-BuONa (2.00 M, 509 uL,2.00 eq), t-BuXPhos Pd G₃ (40.4 mg, 50.9 umol, 0.100 eq) at 20° C. Themixture was degassed and purged with nitrogen for 3 times, and then themixture was stirred at 100° C. for 12 h under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, EtOAc:MeOH=10:1). tert-butyl(S)-4-(2,4-dioxopentan-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(59.7 mg, crude) was obtained as yellow solid.

Step 2: tert-butyl(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-(2,4-dioxopentan-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(59.7 mg, 117 umol, 1.00 eq) in EtOH (2.00 mL) was added methylhydrazine(269 mg, 2.34 mmol, 308 uL, 20.0 eq) at 20° C. Then the mixture wasstirred at 80° C. for 4 h. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, EtOAc:MeOH=5:1). tert-butyl(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(15 mg, crude) was obtained as yellow oil.

Step 3:(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineformate

To tert-butyl(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(15.0 mg, 28.8 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C. Themixture was stirred at 100° C. for 12 h. LC-MS showed tert-butyl(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was concentrated under reduced pressure.The crude product was purified by prep-HPLC (formic acid conditions).(S)-12-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(5.00 mg, 10.6 umol, 36% yield, 98.6% purity, formate salt) was obtainedas yellow solid. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.81 (s, 1H), 7.27 (s, 1H),6.91-6.84 (m, 1H), 6.70-6.64 (m, 1H), 5.19-5.00 (m, 1H), 4.89-4.78 (m,2H), 4.72-4.50 (m, 2H), 4.32-4.20 (m, 1H), 3.98-3.89 (m, 1H), 3.86-3.79(m, 1H), 3.77 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H). LCMS (ESI+): m/z421.2 (M+H).

Example 80:(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-olStep 1: 1-(1H-pyrazol-1-yl)propan-2-one

To a solution of 1H-pyrazole (10.0 g, 147 mmol, 1.00 eq) in1-chloropropan-2-one (20.4 g, 220 mmol, 5.00 mL, 1.50 eq) was addedCs₂CO₃ (14.4 g, 44.2 mmol, 3.01e-1 eq) at 20° C. The mixture was stirredat 90° C. for 6 h. TLC (Petroleum ether:Ethyl acetate=1:1) indicated no1H-pyrazole was remained, and one new spot with lower polarity wasdetected. The reaction mixture was concentrated under reduced pressure.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 1/1). 1-(1H-pyrazol-1-yl)propan-2-one (5.30g, crude) was obtained as yellow oil.

Step 2: 2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol

To a solution of 1-(1H-pyrazol-1-yl)propan-2-one (5.00 g, 40.3 mmol,1.00 eq) in toluene (100 mL) was added Al(CH₃)₃ (2.00 M, 60.4 mL, 3.00eq) at 0° C. under N₂. The mixture was stirred at 50° C. for 6 h. Thereaction mixture was quenched by addition of MeOH (100 mL) at 0° C., andthen the mixture was filtered. The filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 3/2).2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol (2.80 g, crude) was obtained asa white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 7.63 (d, J=2.2 Hz, 1H), 7.39(d, J=0.8 Hz, 1H), 6.21 (t, J=1.6 Hz, 1H), 4.65 (s, 1H), 3.99 (s, 2H),1.01 (s, 6H).

Step 3: 2-methyl-1-(5-(tributylstannyl)-1H-pyrazol-1-yl)propan-2-ol

To a solution of 2-methyl-1-(1H-pyrazol-1-yl)propan-2-ol (200 mg, 1.43mmol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 1.14 mL, 2.00eq) and TMEDA (332 mg, 2.86 mmol, 431 uL, 2.00 eq) at −70° C. under N₂.The mixture was stirred at −70° C. for 30 mins. Thentributyl(chloro)stannane (697 mg, 2.14 mmol, 576 uL, 1.50 eq) was addedto the mixture at −70° C. and the mixture was stirred at 0° C. for 1 hr.The reaction mixture was quenched by addition of MeOH (3.00 mL) at 0° C.And the reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 10/1).2-methyl-1-(5-(tributylstannyl)-1H-pyrazol-1-yl)propan-2-ol (350 mg,crude) was obtained as a yellow liquid.

Step 4:(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(90.0 mg, 230 umol, 1.00 eq) in DMF (4.00 mL) was added LiCl (19.5 mg,460 umol, 2.00 eq), Pd(PPh₃)₄ (26.6 mg, 23.0 umol, 0.100 eq), CuI (18.4mg, 96.6 umol, 0.420 eq) and2-methyl-1-(5-(tributylstannyl)-1H-pyrazol-1-yl)propan-2-ol (148 mg, 345umol, 1.50 eq) at 20° C. under N₂. The mixture was stirred at 80° C. for6 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B %: 15%-45%, 12 min).(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol(28.0 mg, 55.4 umol, 24% yield, 98.3% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-de 400 MHz δ=ppm 9.45 (s, 1H), 7.64 (brt, J=6.4 Hz, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 6.96 (dd, J=10.2, 8.8 Hz,1H), 6.70 (dd, J=8.6, 4.0 Hz, 1H), 6.48 (s, 1H), 4.96-4.87 (m, 1H),4.84-4.74 (m, 1H), 4.58-4.50 (m, 2H), 4.22 (dd, J=9.5, 3.6 Hz, 1H),4.10-3.99 (m, 3H), 3.90-3.79 (m, 1H), 0.93 (s, 6H).

Example 81:(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-(trifluoromethyl)-2-(trimethylstannyl)pyridine

To a solution of 2-bromo-5-(trifluoromethyl)pyridine (240 mg, 1.06 mmol,1.00 eq) and trimethyl (trimethylstannyl) stannane (696 mg, 2.12 mmol,440 uL, 2.00 eq) in dioxane (8.00 mL) was added Pd(PPh₃)₄ (61.4 mg, 53.1umol, 0.0500 eq) under nitrogen atmosphere. The mixture was stirred at100° C. for 2 h under nitrogen atmosphere. LCMS showed the2-bromo-5-(trifluoromethyl)pyridine was consumed completely and thedesired MS was detected.5-(trifluoromethyl)-2-(trimethylstannyl)pyridine (329 mg, crude) wasobtained as yellow liquid (in 8.00 mL of dioxane), which was used to thenext step directly.

Step 2: tert-butyl(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(158 mg, 322 umol, 1.00 eq),5-(trifluoromethyl)-2-(trimethylstannyl)pyridine (329 mg, 1.06 mmol,3.30 eq), LiCl (27.3 mg, 643 umol, 2.00 eq), CuI (24.5 mg, 129 umol,0.400 eq) and Pd(PPh₃)₄ (37.2 mg, 32.2 umol, 0.100 eq) in dioxane (8.00mL) was degassed and purged with nitrogen 3 times, and the mixture wasstirred at 80° C. for 8 h under nitrogen atmosphere. LCMS indicatedincomplete conversion. Pd(PPh₃)₄ (37.2 mg, 32.2 umol, 0.100 eq) wasadded to the mixture under nitrogen atmosphere. The mixture was stirredat 100° C. for 2 h under nitrogen atmosphere. The reaction mixture wasdiluted with water (5.00 mL) and extracted with EtOAc (3.00 mL*3). Thecombined organic layers were washed with brine (5.00 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, PE:EtOAc=1:1). tert-butyl(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50.0 mg, crude) was obtained as yellow oil.

Step 3:(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50.0 mg, 89.7 umol, 1.00 eq) and HFIP (2.00 mL) was stirred at 80° C.for 8 h. LCMS indicated small amount of the starting material remaining.The mixture was stirred at 100° C. for 2 h. LCMS indicated completeconversion. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral conditions).The product-containing fraction was concentrated under reduced pressureto remove most of MeCN at 30° C. and the aqueous phase was lyophilized.QC indicated insufficient purity. The material was re-purified byprep-HPLC (formic acid conditions). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-12-fluoro-4-(5-(trifluoromethyl)pyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(22.3 mg, 43.5 umol, 48% yield, 98.2% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.56 (s, 1H), 9.26 (d,J=8.4 Hz, 1H), 9.00 (s, 1H), 8.43 (s, 1H), 8.36-8.30 (m, 1H), 8.11 (brs, 1H), 6.98 (t, J=9.5 Hz, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 5.03-4.94(m, 1H), 4.89 (s, 1H), 4.60 (br s, 1H), 4.55 (t, J=9.5 Hz, 1H),4.30-4.25 (m, 1H), 4.08 (br s, 1H), 3.98-3.84 (m, 1H). LCMS (ESI+): m/z458.1 (M+H).

Example 82:(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-olStep 1: 1-(3-iodo-1H-pyrazol-1-yl)propan-2-one

To a solution of 3-iodo-1H-pyrazole (2.00 g, 10.3 mmol, 1.00 eq) in MeCN(20.0 mL) was added Cs₂CO₃ (6.72 g, 20.6 mmol, 2.00 eq) and1-chloropropan-2-one (1.43 g, 15.5 mmol, 1.50 eq) at 20° C. The mixturewas stirred at 60° C. for 2 h. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC (column:Phenomenex luna C18 250*50 mm*15 um; mobile phase: [water (0.225%FA)-ACN]; B %: 5%-35%, 20 min). 1-(3-iodo-1H-pyrazol-1-yl)propan-2-one(385 mg, crude) was obtained as a white solid.1-(5-iodo-1H-pyrazol-1-yl)propan-2-one (310 mg, crude) was obtained as awhite solid. ¹H NMR CDCl₃ 400 MHz δ=ppm 7.20 (d, J=2.8 Hz, 1H), 6.44 (d,J=2.0 Hz, 1H), 4.85 (s, 2H), 2.08 (s, 3H).

Step 2: 1-(3-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol

To a solution of 1-(3-iodo-1H-pyrazol-1-yl)propan-2-one (380 mg, 1.52mmol, 1.00 eq) in toluene (10.0 mL) was added AlMe₃ (2.00 M, 3.80 mL,5.00 eq) at 20° C. under N₂. The mixture was stirred at 60° C. for 12 h.LC-MS showed some of 1-(3-iodo-1H-pyrazol-1-yl)propan-2-one remained.The reaction mixture was quenched by addition of MeOH (5.00 mL) at 0° C.Then the mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 4/1).1-(3-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (127 mg, crude) wasobtained as yellow oil.

Step 3: tert-butyl(S)-12-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 157 umol, 1.00 eq) in dioxane (5.00 mL) was added1-(3-iodo-1H-pyrazol-1-yl)-2-methylpropan-2-ol (83.5 mg, 314 umol, 2.00eq), LiCl (13.3 mg, 314 umol, 2.00 eq), Pd(PPh₃)₄ (18.1 mg, 15.7 umol,9.99e-2 eq) and CuI (11.9 mg, 62.5 umol, 3.98e-1 eq) at 20° C. under N₂.The mixture was stirred at 80° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 1/1).tert-butyl(S)-12-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, crude) was obtained as a yellow solid.

Step 4:(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

A mixture of tert-butyl(S)-12-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 145 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C.for 2 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %: 10%-50%, 10min). The product-containing fraction was concentrated under reducedpressure to remove most of MeCN at 30° C. and the aqueous phase waslyophilized to give a yellow solid. The material was additionallypurified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um;mobile phase: [water (0.2% FA)-ACN]; B %: 20%-40%, 10 min).(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol(4.00 mg, 7.80 umol, 5% yield, 96.8% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-cfc 400 MHz δ=ppm 9.42 (s, 1H), 7.81-7.68(m, 2H), 7.46 (br s, 1H), 7.25 (s, 1H), 6.99-6.88 (m, 1H), 6.67 (dd,J=8.8, 3.6 Hz, 1H), 4.93-4.84 (m, 1H), 4.82-4.70 (m, 2H), 4.59-4.48 (m,2H), 4.26 (dd, J=9.5, 3.2 Hz, 1H), 4.09 (s, 2H), 4.03 (br s, 1H),3.91-3.80 (m, 1H), 1.10 (s, 6H) LCMS (ESI+): m/z 451.1 (M+H).

Example 83:(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq) in dioxane (3.00 mL) was added2-bromo-1-methyl-imidazole (91.8 mg, 570 umol, 2.00 eq), Pd(PPh₃)₄ (33.0mg, 28.5 umol, 0.100 eq), CuI (21.7 mg, 114 umol, 0.400 eq), LiCl (24.2mg, 570 umol, 2.00 eq) at 20° C. The mixture was degassed and purgedwith nitrogen 3 times, then the mixture was stirred at 100° C. for 12 hunder nitrogen atmosphere. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, EtOAc:MeOH=10:1). tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, crude) was obtained as a yellow solid.

Step 2:(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 284 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C. Themixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The crude product was purified byprep-HPLC (formic acid conditions). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-12-fluoro-4-(1-methyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(26.2 mg, 59.8 umol, 21% yield, 100% purity, formate salt) was obtainedas yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.84 (s, 1H), 8.38 (s, 1H),7.83 (s, 1H), 7.79 (s, 1H), 6.93 (t, J=9.6 Hz, 1H), 6.69 (dd, J=8.6, 3.9Hz, 1H), 5.26 (br d, J=14.7 Hz, 1H), 5.07 (br s, 1H), 4.78 (br s, 1H),4.63 (br t, J=9.5 Hz, 1H), 4.31 (br d, J=6.1 Hz, 1H), 4.20-4.06 (m, 1H),4.04-3.92 (m, 1H), 3.89 (s, 3H). LCMS (ESI+): m/z 393.1 (M+H).

Example 84:(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine

To a mixture of 4-bromo-5-fluoro-2-methylpyridine (150 mg, 789 umol,1.00 eq), trimethyl(trimethylstannyl)stannane (517 mg, 1.58 mmol, 327uL, 2.00 eq) and Pd(PPh₃)₄ (91.2 mg, 78.9 umol, 0.100 eq) was addeddioxane (3.00 mL) at 20° C. under N₂. Then the mixture was stirred at100° C. for 12 h under nitrogen atmosphere. LC-MS showed4-bromo-5-fluoro-2-methylpyridine was consumed completely and one mainpeak with desired mass was detected. The obtained solution of5-fluoro-2-methyl-4-(trimethylstannyl)pyridine was used in the next stepdirectly.

Step 2: tert-butyl(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine (216 mg,789 umol, 3.23 eq) in dioxane (3.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 244 umol, 1.00 eq), Pd(PPh₃)₄ (28.2 mg, 24.4 umol, 0.100 eq),LiCl (20.7 mg, 488 umol, 2.00 eq) and CuI (18.6 mg, 97.7 umol, 0.400 eq)at 20° C. The mixture was degassed and purged with nitrogen 3 times, andthen the mixture was stirred at 100° C. for 3 h under nitrogenatmosphere. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, EtOAc). tert-butyl(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(130 mg, crude) was obtained as a yellow solid.

Step 3: (S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(130 mg, 249 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C. Themixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The crude product was purified byprep-HPLC (formic acid conditions).(S)-12-fluoro-4-(5-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(57.3 mg, 122 umol, 49% yield, 99.6% purity, formate salt) was obtainedas yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.79 (s, 1H), 9.04 (d, J=4.0Hz, 1H), 8.42 (s, 1H), 8.33 (d, J=6.5 Hz, 1H), 6.93 (dd, J=10.1, 8.9 Hz,1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 5.27-5.21 (m, 1H), 5.13-4.97 (m, 1H),4.92-4.75 (m, 1H), 4.68-4.56 (m, 1H), 4.38-4.27 (m, 1H), 4.19-3.94 (m,2H), 2.89 (s, 3H). LCMS (ESI+): m/z 422.2 (M+H).

Example 85:(S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-2-(difluoromethyl)-4-methylpyridine

To a solution of 5-bromo-4-methylpicolinaldehyde (1.00 g, 5.00 mmol,1.00 eq) in DCM (10.0 mL) was added DAST (3.22 g, 20.0 mmol, 2.64 mL,4.00 eq) at −78° C. The mixture was stirred at −78° C. for 30 min. Thereaction mixture was quenched by addition of sat. aq. Na₂CO₃ (80.0 mL)at 0° C., diluted with water (30.0 mL) and extracted with DCM (30.0mL*3). The combined organic layers were washed with brine (30.0 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 15/1).5-bromo-2-(difluoromethyl)-4-methylpyridine (812 mg, crude) was obtainedas a yellow oil.

Step 2:2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A mixture of 5-bromo-2-(difluoromethyl)-4-methylpyridine (200 mg, 901umol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(343 mg, 1.35 mmol, 1.50 eq), KOAc (265 mg, 2.70 mmol, 3.00 eq),Pd(dppf)Cl₂ (65.9 mg, 90.1 umol, 0.100 eq) in dioxane (2.00 mL) wasdegassed and purged with nitrogen 3 times at 20° C., and then themixture was stirred at 80° C. for 2 h under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 10/1).2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(180 mg, 669 umol, 74% yield) was obtained as yellow oil.

Step 3:(S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(Example 17; 80.0 mg, 205 umol, 1.00 eq) and2-(difluoromethyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(165 mg, 614 umol, 3.00 eq) in dioxane (2.00 mL) and water (0.400 mL)was added Na₂CO₃ (65.0 mg, 614 umol, 3.00 eq) and Pd(dppf)Cl2 (15.0 mg,20.5 umol, 0.100 eq). The mixture was stirred at 80° C. for 2 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was dissolved in MeOH (10.0 mL) and silica-thiol(20.0 mg, modified silicon gel for eliminating Pd, irregular silica gel,100-200 mesh, Chlorides (Cl), %≤0.004, particle size distribution 45-75um) was added at 20° C. and stirred at 20° C. for 4 h. The suspensionwas filtered, the filtrate was concentrated and purified by prep-HPLC(formic acid conditions). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(6-(difluoromethyl)-4-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(32.8 mg, 62.7 umol, 30% yield, 95.4% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.45 (s, 1H), 8.62 (s,1H), 7.68 (s, 1H), 7.62 (t, J=6.4 Hz, 1H), 7.43 (s, 1H), 6.99 (t, J=60.8Hz, 1H), 7.03-6.94 (m, 1H), 6.71 (dd, J=8.7, 3.5 Hz, 1H), 4.98-4.89 (m,1H), 4.86-4.74 (m, 1H), 4.59-4.52 (m, 1H), 4.48 (d, J=8.1 Hz, 1H), 4.22(dd, J=9.5, 3.5 Hz, 1H), 4.05 (s, 1H), 3.94-3.83 (m, 1H), 2.30 (s, 3H).LCMS (ESI+): m/z 454.2 (M+H).

Example 86:(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine

To a stirred solution of 4-bromo-3-fluoro-2-methylpyridine (70.0 mg, 368umol, 1.00 eq) and trimethyl(trimethylstannyl)stannane (241 mg, 737umol, 153 uL, 2.00 eq) in dioxane (3.00 mL) was added Pd(PPh₃)₄ (42.6mg, 36.8 umol, 0.100 eq) at 15° C. under N₂. The resulting mixture wasstirred at 100° C. for 12 h.3-fluoro-2-methyl-4-(trimethylstannyl)pyridine (100 mg, crude) wasobtained as brown liquid (in 3.00 mL dioxane), which was used to thenext step directly.

Step 2: tert-butyl(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine (100 mg,365 umol, 2.00 eq) in dioxane (3.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(89.7 mg, 183 umol, 1.00 eq), LiCl (15.5 mg, 365 umol, 2.00 eq), CuI(13.9 mg, 73.0 umol, 0.400 eq) and Pd(PPh₃)₄ (21.1 mg, 18.3 umol, 0.100eq) at 15° C. under nitrogen atmosphere. The mixture was stirred at 100°C. for 12 h. The mixture was concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE/EtOAc=0/1). tert-butyl(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(60.0 mg, crude) was obtained as a brown solid.

Step 3:(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(60.0 mg, 115 umol, 1.00 eq) was added HFIP (2.00 mL) at 15° C. Theresulting mixture was stirred at 80° C. for 12 h. LCMS showed tert-butyl(S)-12-fluoro-4-(3-fluoro-2-methylpyridin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed and the desired mass was detected. The mixture wasconcentrated under reduced pressure. The mixture was purified by acidicprep-HPLC (FA). The fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized. Thetitle compound (7.10 mg, 14.9 umol, 13% yield, 98.1% purity, formatesalt) was obtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.45(s, 1H), 8.32 (d, J=5.1 Hz, 1H), 7.94 (t, J=5.2 Hz, 1H), 7.84-7.76 (m,1H), 7.64 (s, 1H), 7.00-6.89 (m, 1H), 6.68 (dd, J=8.8, 3.7 Hz, 1H),4.95-4.86 (m, 1H), 4.85-4.75 (m, 1H), 4.55-4.42 (m, 2H), 4.22-4.16 (m,1H), 4.09-3.96 (m, 1H), 3.90-3.79 (m, 1H), 2.50 (s, 3H). ¹H NMR CDCl₃400 MHz δ=ppm 8.84-8.77 (m, 1H), 8.41-8.33 (m, 1H), 8.07-7.99 (m, 1H),7.58-7.52 (m, 1H), 6.92-6.82 (m, 1H), 6.72-6.63 (m, 1H), 5.19-5.08 (m,1H), 4.98-4.81 (m, 2H), 4.69-4.61 (m, 2H), 4.31-4.21 (m, 1H), 3.95-3.80(m, 2H), 2.59 (d, J=3.3 Hz, 3H). LCMS (ESI+): m/z 422.1 (M+H).

Example 87:(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylpropan-2-olStep 1: l-(3-bromopyridin-2-yl)-2-methylpropan-2-ol

To a solution of N-isopropylpropan-2-amine (765 mg, 7.56 mmol, 1.07 mL,1.30 eq) in THF (15.0 mL) was added n-BuLi (2.50 M, 2.79 mL, 1.20 eq) at−70° C. under N₂, and stirred at −70° C. for 0.5 hr.3-Bromo-2-methylpyridine (1.00 g, 5.81 mmol, 1.00 eq) was added to themixture at −70° C. and stirred at −70° C. for 0.5 hr. Acetone (675 mg,11.6 mmol, 854 uL, 2.00 eq) was added to the mixture at −70° C., andstirred at 0° C. for 1 hr. The reaction mixture was quenched by additionof MeOH (7.00 mL) at 0° C. Then the mixture was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 5/1).1-(3-bromopyridin-2-yl)-2-methylpropan-2-ol (1.00 g, crude) was obtainedas yellow oil. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.38 (d, J=4.4 Hz, 1H), 7.81(d, J=8.0 Hz, 1H), 7.00 (dd, J=8.0, 4.8 Hz, 1H), 5.70 (s, 1H), 3.06 (s,2H), 1.20 (s, 6H).

Step 2: 2-methyl-1-(3-(tributylstannyl)pyridin-2-yl)propan-2-ol

To a solution of 1-(3-bromopyridin-2-yl)-2-methylpropan-2-ol (500 mg,2.17 mmol, 1.00 eq) in THF (9.00 mL) was added n-BuLi (2.50 M, 1.74 mL,2.00 eq) and TMEDA (504 mg, 4.34 mmol, 654 uL, 2.00 eq) at −70° C. underN₂. The mixture was stirred at −70° C. for 30 min. Sn(n-BU)₃Cl (1.06 g,3.26 mmol, 877 uL, 1.50 eq) was added at −70° C. and the reactionmixture was stirred at 0° C. for 1 hr. The reaction mixture was quenchedby addition of MeOH (2.00 mL) at 0° C., and then mixture wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 10/1).2-methyl-1-(3-(tributylstannyl)pyridin-2-yl)propan-2-ol (190 mg, crude)was obtained as a yellow liquid.

Step 3: tert-butyl(S)-12-fluoro-4-(2-(2-hydroxy-2-methylpropyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 285 umol, 1.00 eq) in dioxane (3.00 mL) was added2-methyl-1-(3-(tributylstannyl)pyridin-2-yl)propan-2-ol (188 mg, 427umol, 1.50 eq), LiCl (24.2 mg, 571 umol, 2.00 eq), Pd(PPh₃)₄ (36.2 mg,31.3 umol, 0.110 eq) and CuI (21.7 mg, 114 umol, 0.400 eq) at 20° C.under N₂. The mixture was stirred at 80° C. for 3 h. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/2).tert-butyl(S)-12-fluoro-4-(2-(2-hydroxy-2-methylpropyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, crude) was obtained as a brown solid.

Step 4:(S)-1-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)-2-methylpropan-2-ol

A mixture of tert-butyl(S)-12-fluoro-4-(2-(2-hydroxy-2-methylpropyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(60.0 mg, 107 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C.for 2 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30 mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B %: 1%-25%, 12min). The title compound (23.0 mg, 45.3 umol, 42% yield, 99.9% purity,formate salt) was obtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHzδ=ppm 9.43 (s, 1H), 8.56 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=7.6, 1.6Hz, 1H), 7.52 (br t, J=6.4 Hz, 1H), 7.37-7.34 (m, 1H), 7.33 (s, 1H),7.00-6.93 (m, 1H), 6.70 (dd, J=8.6, 4.0 Hz, 1H), 5.43 (br s, 1H),4.97-4.87 (m, 1H), 4.85-4.74 (m, 1H), 4.59-4.51 (m, 1H), 4.48 (br d,J=6.4 Hz, 1H), 4.21 (dd, J=9.6, 3.6 Hz, 1H), 4.08-3.99 (m, 1H),3.90-3.81 (m, 1H), 2.76 (s, 2H), 0.95 (s, 6H). LCMS (ESI+): m/z 462.2(M+H).

Example 88:(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate Step 1:(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a stirred solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(852 mg, 3.83 mmol, 1.50 eq) and Na₂CO₃ (542 mg, 5.11 mmol, 2.00 eq) indioxane (20.0 mL) and water (4.00 mL) was added Pd(dppf)Cl₂ (187 mg, 256umol, 0.100 eq) at 15° C. under N₂. The resulting mixture was stirred at80° C. for 3 h. The mixture was concentrated under reduced pressure. Theresidue was dissolved in DMSO (10.0 mL), MeOH (20.0 mL) and silica-thiol(1.20 g, modified Silicon Gel for Eliminating Pd, Irregular Silica Gel,100-200 mesh, Chlorides (Cl), %≤0.004, Particle Size Distribution 45-75um) was added to the mixture at 15° C. and stirred at 15° C. for 12 h.The suspension was filtered and the filter cake was washed with MeOH(20.0 mL). The filtrate was concentrated under reduced pressure toremove MeOH and purified by acidic prep-HPLC (FA). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(480 mg, 1.18 mmol, 46% yield) was obtained as a white solid.

Step 2:(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate

To(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(480 mg, 1.18 mmol, 1.00 eq) in MeCN (20.0 mL) was added CH₃SO₃H (114mg, 1.18 mmol, 84.1 uL, 1.00 eq) at 15° C. Water (50.0 mL) was added tothe mixture at 15° C. The solution was concentrated under reducedpressure to remove most of MeCN and the aqueous phase was lyophilized.(S)-4-(1,3-dimethyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(525 mg, 1.17 mmol, 99% yield, 99.1% purity, 0.4 eq. CH₃SO₃H) wasobtained as a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.51 (s, 1H),7.96 (brs, 1H), 7.59 (s, 1H), 6.96 (t, 7=9.5 Hz, 1H), 6.69 (dd, J=8.6,3.7 Hz, 1H), 6.31 (s, 1H), 4.99-4.87 (m, 1H), 4.86-4.75 (m, 1H),4.58-4.45 (m, 2H), 4.19 (br dd, J=9.6, 3.4 Hz, 1H), 4.04 (br d, J=9.9Hz, 2H), 3.89-3.82 (m, 1H), 3.69 (s, 3H), 2.28 (s, 1.2H), 2.17 (s, 3H).LCMS (ESI+): m/z 407.1 (M+H).

Example 89:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,1-dimethyl-1H-pyrazol-3-amineStep 1: tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate

To a solution of 5-bromo-1-methyl-1H-pyrazol-3-amine (300 mg, 1.70 mmol,1.00 eq) in THF (8.00 mL) was added TEA (345 mg, 3.41 mmol, 475 uL, 2.00eq) and Boc₂O (893 mg, 4.09 mmol, 940 uL, 2.40 eq) at 20° C. The mixturewas stirred at 80° C. for 6 h. The reaction was concentrated. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=3/1). tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate(270 mg, 978 umol, 57% yield) was obtained as a white solid.

Step 2: tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)(methyl)carbamate

To a mixture of tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate(270 mg, 978 umol, 1.00 eq) in THF (6.00 mL) was added NaH (78.2 mg,1.96 mmol, 60.0% purity, 2.00 eq) at 0° C. The mixture was stirred at 0°C. for 0.5 hr. Then Mel (278 mg, 1.96 mmol, 122 uL, 2.00 eq) was addedto the mixture at 0° C., the mixture was stirred at 20° C. for 12 h.Water (5.00 mL) was added to the reaction solution, the mixture wasextracted with ethyl acetate (5.00 mL*3), the combined organic layerswere dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=3/1). tert-butyl(5-bromo-1-methyl-1H-pyrazol-3-yl)(methyl)carbamate (150 mg, 517 umol,52% yield) was obtained as a yellow oil.

Step 3: tert-butylmethyl(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)carbamate

To a solution of tert-butyl(5-bromo-1-methyl-1H-pyrazol-3-yl)(methyl)carbamate (150 mg, 517 umol,1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 620 uL, 3.00 eq) at−70° C. The mixture was stirred at −70° C. for 0.5 hr. Thentributyl(chloro)stannane (673 mg, 2.07 mmol, 556 uL, 4.00 eq) was addedto the mixture at −70° C. under nitrogen atmosphere and the mixture wasstirred at 20° C. for 12 h. Water (5.00 mL) was added to the reactionsolution, the mixture was extracted with ethyl acetate (5.00 mL*3), thecombined organic layers were dried over MgSO₄, and concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=3/1). tert-butylmethyl(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)carbamate (200 mg,400 umol, 77% yield) was obtained as a yellow oil.

Step 4: tert-butyl(S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 204 umol, 1.00 eq) in dioxane (6.00 mL) were added tert-butylmethy 1(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)carbamate (175 mg,350 umol, 1.72 eq), CuI (15.5 mg, 81.4 umol, 0.400 eq) and LiCl (17.3mg, 407 umol, 2.00 eq) Pd(PPh₃)₄ (23.5 mg, 20.4 umol, 0.100 eq) at 20°C. under nitrogen atmosphere. The mixture was stirred at 90° C. for 12 hunder nitrogen atmosphere. The reaction was filtered, the filtrate wasconcentrated. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=0/1). tert-butyl(S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 193 umol, 94% yield) was obtained as a yellow solid. Inaddition, 60 mg of crude product and 30 mg of crude deprotected materialwere obtained.

Step 5:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-NA-dimethyl-1H-pyrazol-3-amine

A mixture of tert-butyl(S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 193 umol, 1.00 eq) in DCM (4.00 mL) and TFA (2.00 mL) wasstirred at 20° C. for 12 h. The reaction was concentrated. The residuewas dissolved in DMSO (3.00 mL). The suspension was purified by acidicprep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 15%-40%, 10 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,1-dimethyl-1H-pyrazol-3-amine(37.0 mg, 76.6 umol, 39% yield, 94.8% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.55 (s, 1H), 8.05 (s, 1H),7.02-6.89 (m, 1H), 6.70 (dd, 7=8.7, 3.9 Hz, 1H), 6.44 (s, 1H), 5.22 (d,7=14.5 Hz, 1H), 4.98 (br d, 7=14.8 Hz, 1H), 4.78 (brs, 1H), 4.64 (t,7=9.5 Hz, 1H), 4.33 (dd, 7=9.7, 3.3 Hz, 1H), 4.06 (br d, 7=8.8 Hz, 1H),3.97-3.86 (m, 1H), 3.77 (s, 3H), 3.07 (s, 3H). LCMS (ESI+): m/z 422.2(M+H).

Example 90:(R)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(enantiomer of Example 17; obtained via the same sequence using(R)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate in the Example 6procedure) (200 mg, 511 umol, 1.00 eq),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (224mg, 1.02 mmol, 2.00 eq), Pd(dppf)Cl₂ (37.4 mg, 51.1 umol, 0.100 eq) andNaHCO₃ (85.9 mg, 1.02 mmol, 39.8 uL, 2.00 eq) in dioxane (4.00 mL) andwater (0.400 mL) was degassed and purged with nitrogen 3 times at 20°C., and then the mixture was stirred at 80° C. for 12 h under nitrogenatmosphere. Silica-thiol (100 mg, modified silicon gel for eliminatingPd, irregular silica gel, 100-200 mesh, Chlorides (Cl), %≤0.004,particle size distribution 45-75 um) was added to the reaction mixtureat 20° C. and stirred at 20° C. for 2 h. The mixture was concentratedunder reduced pressure. The residue was dissolved in DMSO (4.00 mL), thesuspension was filtered, the filtrate was concentrated and purified byacidic prep-HPLC (HCl conditions, column: Phenomenex Luna C18 150*30mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B %: 20%-40%, 10 min.The fraction was lyophilized.(R)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(68.5 mg, 155 umol, 30% yield, 99.8% purity, HCl salt) was obtained as ayellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.70 (d, J=2.4 Hz, 1H), 8.81(d, J=5.5 Hz, 1H), 8.52 (br d, J=7.3 Hz, 1H), 8.32-8.23 (m, 1H), 7.92(br t, J=6.8 Hz, 1H), 7.72 (s, 1H), 7.06-6.93 (m, 1H), 6.71 (dd, J=8.7,3.9 Hz, 1H), 5.02-4.91 (m, 1H), 4.89-4.77 (m, 1H), 4.60-4.47 (m, 2H),4.22 (dd, J=9.7, 3.3 Hz, 1H), 4.12-4.00 (m, 1H), 3.92-3.85 (m, 1H), 2.64(s, 3H).

Example 91:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N,1-trimethyl-1H-pyrazol-3-amineStep 1: 5-bromo-N,N,1-trimethyl-1H-pyrazol-3-amine

To a solution of 5-bromo-1-methyl-1H-pyrazol-3-amine (200 mg, 1.14 mmol,1.00 eq) and 37% aqueous HCHO (369 mg, 4.55 mmol, 338 uL, 4.00 eq) inMeOH (5.00 mL) was added AcOH (6.82 mg, 114 umol, 6.50 uL, 0.100 eq) at20° C. The mixture was stirred at 20° C. for 1 hr. Then NaBH₃CN (179 mg,2.84 mmol, 2.50 eq) was added to the mixture, and the mixture wasstirred at 20° C. for 10 h. The reaction mixture was concentrated underreduced pressure. The residue was dissolved with DCM (8.00 mL), washedwith saturated aqueous sodium bicarbonate (3.00 mL). The organic layerwas dried over Na₂SO₄ and then concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether:Ethylacetate=2:1). 5-bromo-N,N,1-trimethyl-1H-pyrazol-3-amine (180 mg, 882umol, 77% yield) was obtained as a light yellow oil.

Step 2: N,N,1-trimethyl-5-(tributylstannyl)-1H-pyrazol-3-amine

To a solution of 5-bromo-N,N,1-trimethyl-1H-pyrazol-3-amine (180 mg, 882umol, 1.00 eq) in THF (6.00 mL) was added dropwised n-BuLi (2.50 M, 529uL, 1.50 eq) at −78° C. The mixture was stirred at −78° C. for 0.5 hr.Then tributyl(chloro)stannane (861 mg, 2.65 mmol, 712 uL, 3.00 eq) wasadded to the mixture at −78° C., and the mixture was stirred at −78° C.for 1 hr. The reaction mixture was quenched by saturated aqueous NH₄Clsolution (2.00 mL) at 0° C., then diluted with water (5.00 mL),extracted with ethyl acetate (4.00 mL*3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Petroleum ether:Ethyl acetate=4:1).N,N-1-trimethyl-5-(tributylstannyl)-1H-pyrazol-3-amine (200 mg, 483umol, 54% yield) was obtained as a colourless oil.

Step 3: tert-butyl(S)-4-(3-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of N,N,1-trimethyl-5-(tributylstannyl)-1H-pyrazol-3-amine (194mg, 468 umol, 1.15 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq), LiCl (25.9 mg, 611 umol, 1.50 eq), CuI(38.8 mg, 204 umol, 0.500 eq) and Pd(PPh₃)₄ (23.5 mg, 20.4 umol, 0.0500eq) in dioxane (5.00 mL) was degassed and purged with nitrogen 3 timesat 20° C., and then the mixture was stirred at 80° C. for 10 h undernitrogen atmosphere. The reaction mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Ethyl acetate:Methanol=8:1). tert-butyl(S)-4-(3-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 373 umol, 91% yield) was obtained as a yellow solid.

Step 4:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N,1-trimethyl-1H-pyrazol-3-amine

To a solution of tert-butyl(S)-4-(3-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 373 umol, 1.00 eq) in DCM (4.00 mL) was added TFA (4.62 g, 40.5mmol, 3.00 mL, 109 eq) at 20° C. The mixture was stirred at 20° C. for 3h. LC-MS showed tert-butyl(S)-4-(3-(dimethylamino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (formic acid conditions) (column:Phenomenex Synergi C18 150*25 mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 20%-50%, 12 min).(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N,1-trimethyl-1H-pyrazol-3-amine(102 mg, 210 umol, 56% yield, 99.6% purity, formate salt) was obtainedas a white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.43 (s, 1H), 8.13 (s,1H), 7.67-7.58 (m, 1H), 7.37 (s, 1H), 6.96 (t, J=9.6 Hz, 1H), 6.69 (dd,J=8.5, 3.6 Hz, 1H), 5.94 (s, 1H), 4.94-4.85 (m, 1H), 4.83-4.71 (m, 1H),4.58-4.39 (m, 2H), 4.20 (br d, J=9.7 Hz, 1H), 4.03 (br s, 1H), 3.92-3.79(m, 1H), 3.62 (s, 3H), 2.75 (s, 6H). LCMS (ESI+): m/z 436.2 (M+H).

Example 92:(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-methoxy-6-(tributylstannyl)pyridine

To a solution of 2-bromo-6-methoxypyridine (300 mg, 1.60 mmol, 196 uL,1.00 eq) in THF (6.00 mL) was added n-BuLi (2.50 M, 1.28 mL, 2.00 eq) at−78° C. Then the mixture was stirred at −78° C. for 0.5 hr.Tributyl(chloro)stannane (779 mg, 2.39 mmol, 644 uL, 1.50 eq) was addedto the mixture, and the mixture was stirred at −78° C. for 2 h. Thereaction mixture was quenched by saturated aqueous NH₄Cl solution (2.00mL) at 0° C. then diluted with water (6.00 mL) and extracted with ethylacetate (5.00 mL*3). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether:Ethyl acetate=10:1). 2-methoxy-6-(tributylstannyl)pyridine (300mg, 753 umol, 47% yield) was obtained as a colourless oil.

Step 2: tert-butyl(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 2-methoxy-6-(tributylstannyl)pyridine (146 mg, 366 umol,1.20 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), LiCl (19.4 mg, 458 umol, 9.38 uL, 1.50 eq),CuI (29.1 mg, 153 umol, 0.500 eq) and Pd(PPh₃)₄ (17.6 mg, 15.3 umol,0.0500 eq) in dioxane (4.00 mL) was degassed and purged with nitrogenfor 3 times at 20° C., and then the mixture was stirred at 80° C. for 10h under nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure. The residue was purified by prep-TLC (SiO₂, Petroleumether:Ethyl acetate=1:1). tert-butyl(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(130 mg, 250 umol, 82% yield) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 192 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80° C. for3 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC (formicacid conditions) (column: Phenomenex Luna C18 200*40 mm*10 um; mobilephase: [water (0.2% FA)-ACN]; B %: 30%-60%, 10 min).(S)-12-fluoro-4-(6-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(34.9 mg, 74.5 umol, 38% yield, 99.3% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.50 (s, 1H), 8.66 (d,J=7.5 Hz, 1H), 8.32 (s, 1H), 7.85-7.75 (m, 2H), 7.01-6.94 (m, 1H), 6.74(d, J=8.2 Hz, 1H), 6.70 (dd, J=8.7, 3.6 Hz, 1H), 4.98-4.80 (m, 2H), 4.53(br t, J=9.4 Hz, 2H), 4.26 (br d, J=6.2 Hz, 1H), 4.08 (br s, 1H), 4.00(s, 3H), 3.98-3.90 (m, 1H). LCMS (ESI+): m/z 420.1 (M+H).

Example 93:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-amineStep 1: tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate

Two parallel reactions were set up. To a solution of5-bromo-1-methyl-1H-pyrazol-3-amine (350 mg, 1.99 mmol, 1.00 eq) in THF(6.00 mL) was added TEA (403 mg, 3.98 mmol, 554 uL, 2.00 eq) and Boc₂O(1.04 g, 4.77 mmol, 1.10 mL, 2.40 eq) at 20° C. The mixture was stirredat 80° C. for 12 h. The batches were combined and the obtained mixturewas concentrated. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 3/1). tert-butyl(5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (760 mg, 2.75 mmol, 69%yield) was obtained as a white solid.

Step 2: tert-butyl(1-methyl-5-(trimethylstannyl)-1H-pyrazol-3-yl)carbamate

To a solution of tert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate(240 mg, 869 umol, 1.00 eq) in dioxane (15.0 mL) was addedtrimethyl(trimethylstannyl)stannane (570 mg, 1.74 mmol, 361 uL, 2.00 eq)and Pd(PPh₃)₄ (100 mg, 86.9 umol, 0.100 eq) at 20° C. The mixture wasstirred at 100° C. for 12 h under nitrogen atmosphere. LCMS showedtert-butyl (5-bromo-1-methyl-1H-pyrazol-3-yl)carbamate was remained andthe desired mass was detected. tert-butyl(1-methyl-5-(trimethylstannyl)-1H-pyrazol-3-yl)carbamate (310 mg, crude)in dioxane (15.0 mL) as a brown liquid used for next step directly.

Step 3: tert-butyl(S)-4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(1-methyl-5-(trimethylstannyl)-1H-pyrazol-3-yl)carbamate (300 mg, 833umol, 2.00 eq) in dioxane (14.5 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(205 mg, 417 umol, 1.00 eq), Pd(PPh₃)₄ (48.1 mg, 41.7 umol, 0.100 eq),CuI (31.7 mg, 167 umol, 0.400 eq) and LiCl (35.3 mg, 833 umol, 17.1 uL,2.00 eq) at 20° C. The mixture was stirred at 100° C. for 12 h undernitrogen atmosphere. The reaction was filtered, the filtrate wasconcentrated. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=1/1). tert-butyl(S)-4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(270 mg, crude) was obtained as a yellow oil.

Step 4:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-amine

A mixture of tert-butyl(S)-4-(3-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(270 mg, 444 umol, 1.00 eq) in TFA (2.50 mL) and DCM (5.00 mL) wasstirred at 20° C. for 6 h. The reaction was concentrated. The residuewas dissolved in MeOH (5.00 mL), the suspension was filtered, thefiltrate was concentrated and purified by neutral prep-HPLC (column:Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 5%-35%, 10 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-amine(20.3 mg, 49.7 umol, 11% yield, 99.7% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (s, 1H), 7.59 (br t, J=6.4 Hz,1H), 7.34 (s, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.70 (dd, J=8.6, 3.8 Hz, 1H),5.76 (s, 1H), 4.97-4.86 (m, 1H), 4.84-4.73 (m, 1H), 4.59 (s, 2H), 4.54(br t, J=9.4 Hz, 1H), 4.49 (br s, 1H), 4.21 (br dd, J=9.7, 3.4 Hz, 1H),4.04 (br s, 1H), 3.91-3.82 (m, 1H), 3.56 (s, 3H). LCMS (ESI+): m/z 408.1(M+H).

Example 94:(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Two parallel reactions were set up. A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 171 umol, 1.00 eq), 4-bromo-1-methyl-imidazole (82.6 mg, 513umol, 3.00 eq), palladium tritert-butylphosphane (8.74 mg, 17.1 umol,0.100 eq) in dioxane (2.00 mL) was degassed and purged with nitrogen for3 times at 20° C., and then the mixture was stirred at 100° C. for 4 hunder nitrogen atmosphere. The batches were combined. The reactionmixture was diluted with water (5.00 mL) and extracted with EtOAc (5.00mL*3). The combined organic layers were washed with brine (3.00 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, EtOAc:MeOH=5:1). tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50 mg, crude) was obtained as a yellow oil.

Step 2:(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50.0 mg, 102 umol, 1.00 eq) and HFIP (2.00 mL) was stirred at 80° C.for 8 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC (HClcondition). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-12-fluoro-4-(1-methyl-1H-imidazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(16.0 mg, 37.1 umol, 36% yield, 99.3% purity, HCl) was obtained as ayellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.61 (s, 1H), 9.17 (s, 1H),8.36 (s, 1H), 8.18 (s, 1H), 8.10-8.00 (m, 1H), 6.93 (t, J=9.5 Hz, 1H),6.67 (dd, J=8.5, 3.9 Hz, 1H), 4.93-4.85 (m, 1H), 4.80 (s, 1H), 4.56-4.45(m, 2H), 4.21 (d, J=9.7 Hz, 1H), 4.03 (s, 1H), 3.92 (s, 3H), 3.88-3.80(m, 1H). ¹H NMR CD₃OD 400 MHz δ=ppm 9.60 (s, 1H), 9.07 (s, 1H), 8.11 (s,1H), 8.06 (s, 1H), 6.88 (t, J=9.5 Hz, 1H), 6.65 (dd, J=8.6, 3.7 Hz, 1H),5.14 (d, J=15.0 Hz, 1H), 4.93 (d, J=15.0 Hz, 1H), 4.76 (d, J=5.3 Hz,1H), 4.61 (t, J=9.3 Hz, 1H), 4.31 (dd, J=9.6, 2.8 Hz, 1H), 4.10-4.04 (m,1H), 4.03 (s, 3H), 3.98-3.90 (m, 1H). LCMS (ESI+): m/z 393.2 (M+H).

Example 95:(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 1,2-dimethyl-5-(tributylstannyl)-1H-imidazole

To a solution of 5-bromo-1,2-dimethyl-1H-imidazole (250 mg, 1.43 mmol,1.00 eq) in THF (2.00 mL) was added n-BuLi (2.50 M, 1.14 mL, 2.00 eq) at−78° C. under nitrogen atmosphere. The mixture was stirred at −78° C.for 0.5 hr. Then tributyl(chloro)stannane (1.86 g, 5.71 mmol, 1.54 mL,4.00 eq) was added to the mixture under nitrogen atmosphere at −78° C.,and the mixture was stirred at −78° C. for 1 hr under nitrogenatmosphere. Then the mixture was warmed slowly to 20° C. The mixture wasstirred at 20° C. for 10 h under nitrogen atmosphere. The reactionmixture was quenched by saturated aqueous NH₄Cl solution (4.00 mL) at 0°C., then diluted with water (5.00 mL), and extracted with ethyl acetate(5.00 mL*3). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toafford a crude product. 1,2-dimethyl-5-(tributylstannyl)-1H-imidazole(500 mg, crude) was obtained as a yellow gum.

Step 2: tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 1,2-dimethyl-5-(tributylstannyl)-1H-imidazole (470 mg, 1.22mmol, 4.00 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), LiCl (19.4 mg, 458 umol, 1.50 eq), CuI(29.1 mg, 153 umol, 0.500 eq) and Pd(PPh₃)₄ (17.6 mg, 15.3 umol, 0.0500eq) in dioxane (6.00 mL) was degassed and purged with nitrogen 3 timesat 20° C., and then the mixture was stirred at 80° C. for 10 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂, Ethylacetate/Methanol=1/0 to 3/1). tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 296 umol, 97% yield) was obtained as a yellow solid.

Step 3:(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate3(130 mg, 257 umol, 1.00 eq) in DCM (3.00 mL) was added TFA (2.31 g, 20.3mmol, 1.50 mL, 78.9 eq) at 20° C. The mixture was stirred at 20° C. for3 h The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (formic acid conditions).(S)-4-(1,2-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(79.5 mg, 174 umol, 67% yield, 99.2% purity, formate salt) was obtainedas a light yellow solid. ¹H NMR DMSO-d₆ 400 MHz 3=ppm 9.49 (s, 1H), 7.89(br t, 7=6.1 Hz, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.02-6.90 (m, 1H),6.71 (dd, J=8.7, 3.8 Hz, 1H) 4.99-4.89 (m, 1H), 4.87-4.74 (m, 1H),4.60-4.43 (m, 2H), 4.22 (br dd, J=9.5, 3.3 Hz, 1H), 4.04 (br s, 1H),3.87 (br t, J=10.9 Hz, 1H), 3.65 (s, 3H), 2.66 (s, 3H). LCMS (ESI+): m/z407.1 (M+H).

Example 96:(S)-4-(4,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: (4,6-dimethylpyridin-3-yl)boronic acid

To a solution of 5-bromo-2,4-dimethylpyridine (400 mg, 2.15 mmol, 1.00eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 1.12 mL, 1.30 eq) at −65°C. and stirred at −65° C. for 0.5 hr. Triisopropyl borate (809 mg, 4.30mmol, 989 uL, 2.00 eq) was added to the solution and the reactionmixture was stirred at −65° C. for 1 hr. MeOH (2.00 mL) was added to thesolution and the mixture was concentrated.(4,6-dimethylpyridin-3-yl)boronic acid (400 mg, crude) was obtained as awhite solid.

Step 2:(S)-4-(4,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of (4,6-dimethylpyridin-3-yl)boronic acid (116 mg, 767umol, 3.00 eq) in EtOH (5.00 mL) and water (1.00 mL) was added(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq), KOAc (75.3 mg, 767 umol, 3.00 eq) and4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (18.1mg, 25.6 umol, 18.1 uL, 0.100 eq) at 20° C. under nitrogen atmosphere.The mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in MeOH (10.0 mL) and silica-thiol (20.0 mg, modifiedsilicon gel for eliminating Pd, irregular silica gel, 100-200 mesh,Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) was addedat 20° C. and stirred at 20° C. for 4 h. The suspension was filtered,the filtrate was concentrated and purified by prep-HPLC (formic acidconditions). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-4-(4,6-dimethylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(26.0 mg, 56.1 umol, 22% yield, 100% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.39 (s, 1H), 8.33 (s,1H), 7.48 (t, 7=6.3 Hz, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 6.95 (dd,J=10.3, 8.9 Hz, 1H), 6.68 (dd, J=8.6, 3.7 Hz, 1H), 4.95-4.83 (m, 1H),4.82-4.71 (m, 1H), 4.57-4.49 (m, 1H), 4.45 (d, J=5.7 Hz, 1H), 4.19 (dd,J=9.5, 3.5 Hz, 1H), 4.00 (d, J=9.3 Hz, 1H), 3.90-3.76 (m, 1H), 2.45 (s,3H), 2.14 (s, 3H). LCMS (ESI+): m/z 418.1 (M+H).

Example 97:(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-4-iodo-2-methylpyridine

To a stirred solution of 5-bromo-2-methylpyridin-4-amine (2.05 g, 11.0mmol, 1.00 eq) and diiodomethane (5.87 g, 21.9 mmol, 1.77 mL, 2.00 eq)in MeCN (20.0 mL) was added isopentyl nitrite (2.82 g, 24.1 mmol, 3.25mL, 2.20 eq) in MeCN (10.0 mL) at 0° C. The resulting mixture wasstirred at 0° C. for 1 hr and then stirred at 60° C. for 12 h. Themixture was concentrated under reduced pressure. The mixture waspurified by MPLC (SiO₂, PE/EtOAc=1/0 to 3/1).5-bromo-4-iodo-2-methylpyridine (1.50 g, 5.03 mmol, 45% yield) wasobtained as a yellow solid.

Step 2: 5-bromo-2-methyl-4-vinylpyridine

To a stirred solution of 5-bromo-4-iodo-2-methylpyridine (1.50 g, 5.03mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (620 mg,4.03 mmol, 683 uL, 0.800 eq) and Na₂CO₃ (1.07 g, 10.1 mmol, 2.00 eq) indioxane (20.0 mL) and water (4.00 mL) was added Pd(dppf)Cl₂ (369 mg, 504umol, 0.100 eq) at 15° C. under N₂. The resulting mixture was stirred at80° C. for 12 h. LCMS indicated incomplete conversion. To the mixturewas added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.200 eq) andPd(dppf)Cl₂ (0.100 eq) at 15° C. under N₂. The resulting mixture wasstirred at 80° C. for 2 h. LCMS showed that5-bromo-4-iodo-2-methylpyridine was consumed completely. The mixture wasconcentrated under reduced pressure. The mixture was purified by MPLC(SiO₂, PE/EtOAc=1/0 to 3/1). 5-bromo-2-methyl-4-vinylpyridine (900 mg,4.54 mmol, 90% yield) was obtained as yellow oil.

Step 3: 5-bromo-2-methylisonicotinaldehyde

Ozone (15 psi) was bubbled into a solution of5-bromo-2-methyl-4-vinylpyridine (900 mg, 4.54 mmol, 1.00 eq) in DCM(30.0 mL) at −78° C. for 0.5 hr. After excess O₃ was purged by O₂ (15psi) for 0.5 hr, to the mixture was added Me₂S (5.65 g, 90.9 mmol, 6.67mL, 20.0 eq) at −78° C. The resulting mixture was stirred at 15° C. for2 h. The mixture was concentrated under reduced pressure. The mixturewas purified by MPLC (SiO₂, PE/EtOAc=1/0 to 1/1).5-bromo-2-methylisonicotinaldehyde (450 mg, 2.25 mmol, 49% yield) wasobtained as a white solid.

Step 4: 5-bromo-4-(difluoromethyl)-2-methylpyridine

To a stirred solution of 5-bromo-2-methylisonicotinaldehyde (450 mg,2.25 mmol, 1.00 eq) in DCM (5.00 mL) was added DAST (798 mg, 4.95 mmol,654 uL, 2.20 eq) at −78° C. under N₂. The resulting mixture was stirredat 15° C. for 12 h. The mixture was basified by saturated aqueous NaHCO₃solution to pH=7-8 and the mixture was extracted with EtOAc (10.0 mL*3).The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The mixture was purified by MPLC (SiO₂,PE/EtOAc=1/0 to 3/1). 5-bromo-4-(difluoromethyl)-2-methylpyridine (210mg, 946 umol, 42% yield) was obtained as yellow oil. ¹H NMR CDCl₃ 400MHz δ=ppm 8.66 (s, 1H), 7.40 (s, 1H), 6.79 (t, J=54.4 Hz, 1H), 2.58 (s,3H).

Step 5: 4-(difluoromethyl)-2-methyl-5-(tributylstannyl)pyridine

To a solution of 5-bromo-4-(difluoromethyl)-2-methylpyridine (190 mg,856 umol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 377 uL,1.10 eq) at −78° C. under nitrogen and the mixture was stirred at −78°C. for 0.5 hr under N₂. Tributyl(chloro)stannane (836 mg, 2.57 mmol, 691uL, 3.00 eq) was added to the mixture under nitrogen atmosphere at −78°C. and the resulting mixture was stirred at −78° C. for 2 h under N₂.The mixture was quenched with saturated aqueous NH₄Cl solution (5.00 mL)and the mixture was extracted with EtOAc (5.00 mL*3). The combinedorganic layers were dried over Na₂SO₄ and then concentrated underreduced pressure. The mixture was purified by MPLC (SiO₂, PE/EtOAc=1/0to 1/1). 4-(difluoromethyl)-2-methyl-5-(tributylstannyl)pyridine (120mg, 278 umol, 32% yield) was obtained as yellow oil.

Step 6: tert-butyl(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of4-(difluoromethyl)-2-methyl-5-(tributylstannyl)pyridine (120 mg, 278umol, 1.00 eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(136 mg, 278 umol, 1.00 eq) in dioxane (4.00 mL) was added CuI (21.2 mg,111 umol, 0.400 eq), LiCl (23.5 mg, 555 umol, 11.4 uL, 2.00 eq) andPd(PPh₃)₄ (32.1 mg, 27.8 umol, 0.100 eq) at 20° C. under N₂. Theresulting mixture was stirred at 100° C. for 12 h. The mixture wasconcentrated under reduced pressure. The mixture was purified byprep-TLC (SiO₂, PE/EtOAc=0/1). tert-butyl(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, crude) was obtained as a yellow solid.

Step 7:(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 271 umol, 1.00 eq) was added HFIP (3.00 mL) at 20° C. Themixture was concentrated under reduced pressure. The mixture waspurified by acidic prep-HPLC (HCl conditions). HPLC analysis indicatedinsufficient purity. The material was additionally purified by acidicprep-HPLC (FA). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-4-(4-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(20.9 mg, 45.5 umol, 16% yield, 98.6% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (s, 1H), 8.63 (s, 1H), 7.61 (brt, J=6.4 Hz, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.05 (t, J=54.4 Hz, 1H),6.96 (dd, J=10.0, 8.8 Hz, 1H), 6.69 (dd, J=8.7, 3.9 Hz, 1H), 4.96-4.87(m, 1H), 4.85-4.72 (m, 1H), 4.58-4.42 (m, 2H), 4.20 (dd, J=9.6, 3.4 Hz,1H), 4.07-3.96 (m, 1H), 3.93-3.84 (m, 1H), 2.59 (s, 3H). LCMS (ESI+):m/z 454.2 (M+H).

Example 98:(S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)methanamineStep 1: (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol

To a solution of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (5.20g, 23.7 mmol, 1.00 eq) in DCM (200 mL) was added DIBAL-H (1.00 M, 47.5mL, 2.00 eq) at −65° C. under N₂ and stirred at −65° C. for 1 hr. TLC(Petroleum ether/Ethyl acetate=3/1) showed that the reaction wascomplete. The mixture was added dropwise to sat. aq. potassium sodiumtartrate (200 mL), stirred for 0.5 hr at 20° C., then extracted with DCM(200 mL*3). The combined organic layers were dried over Na₂SO₄ andconcentrated. (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol (4.50 g, crude)was obtained as yellow oil.

Step 2: 5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde

To a solution of (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol (4.50 g,23.6 mmol, 1.00 eq) in DCM (100 mL) was added DMP (20.0 g, 47.1 mmol,14.6 mL, 2.00 eq) at 0° C., stirred at 20° C. for 12 h. The mixture wasfiltered, the filtrate was concentrated. The residue was purified byMPLC (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1).5-Bromo-1-methyl-1H-pyrazole-3-carbaldehyde (2.70 g, 14.3 mmol, 60%yield) was obtained as a white solid.

Step 3: 5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde oxime

To a solution of 5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g,5.29 mmol, 1.00 eq) in DCM (10.0 mL) was added hydroxylaminehydrochloride (735 mg, 10.6 mmol, 2.00 eq), TEA (2.14 g, 21.2 mmol, 2.95mL, 4.00 eq) at 20° C., and the mixture was stirred at 20° C. for 1 hr.TLC (Petroleum ether/Ethyl acetate=3/1) showed that the reaction wascomplete. Water (5.00 mL) was added to the solution and the mixture wasextracted with DCM (10.0 mL*3). The combined organic layers were driedover Na₂SO₄ and concentrated.5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde oxime (1.15 g, crude) wasobtained as a yellow oil.

Step 4: (5-bromo-1-methyl-1H-pyrazol-3-yl)methanamine

To a solution of 5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde oxime (1.00g, 4.90 mmol, 1.00 eq) in AcOH (10.0 mL) was added to Zn (3.21 g, 49.0mmol, 10.0 eq) at 20° C. and the mixture was stirred at 20° C. for 12 h.MeOH (10.0 mL) was added to the solution which was then filtered and thefiltrate was concentrated. 1.20 g of crude(5-bromo-1-methyl-1H-pyrazol-3-yl)methanamine (AcOH salt) including(1-methyl-1H-pyrazol-3-yl)methanamine was obtained as a yellow oil.

Step 5: tert-butyl ((5-bromo-1-methyl-1H-pyrazol-3-yl)methyl)carbamate

To a solution of (5-bromo-1-methyl-1H-pyrazol-3-yl)methanamine (1.20 g,4.80 mmol, 1.00 eq, HOAc) in DCM (20.0 mL) was added TEA (3.88 g, 38.4mmol, 5.34 mL, 8.00 eq), (BOC)₂O (1.57 g, 7.20 mmol, 1.65 mL, 1.50 eq)at 20° C., then the mixture was stirred at 20° C. for 2 h. The mixturewas concentrated. The residue was purified by MPLC (SiO₂, Petroleumether/Ethyl acetate=1/0 to 0/1). tert-butyl((5-bromo-1-methyl-1H-pyrazol-3-yl)methyl)carbamate (300 mg, 1.03 mmol,21% yield) was obtained as a yellow oil.

Step 6: tert-butyl((1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)methyl)carbamate

To a solution of tert-butyl((5-bromo-1-methyl-1H-pyrazol-3-yl)methyl)carbamate (250 mg, 862 umol,1.00 eq) in THF (6.00 mL) was added n-BuLi (2.50 M, 689 uL, 2.00 eq) at−65° C. under N₂ and the reaction mixture was stirred at −65° C. for 0.5hr. Sn(n-Bu)₃Cl (1.12 g, 3.45 mmol, 927 uL, 4.00 eq) was added to thesolution at −65° C. and the mixture was stirred at −65° C. for 1 hrunder N₂. LCMS showed the reaction was complete. Sat. aq. NH₄Cl (4.00mL) was added to the solution, then the mixture was extracted with EtOAc(4.00 mL*3), the combined organic layers was dried over Na₂SO₄, thenconcentrated, tert-butyl((1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)methyl)carbamate (430 mg,crude) was obtained as a yellow oil.

Step 7: tert-butyl(S)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl((1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)methyl)carbamate (430 mg,859 umol, 1.92 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(220 mg, 448 umol, 1.00 eq) in dioxane (4.00 mL) was added LiCl (1.90mg, 44.8 umol, 0.100 eq), CuI (8.53 mg, 44.8 umol, 0.100 eq) andPd(PPh₃)₄ (51.7 mg, 44.8 umol, 0.100 eq) at 20° C. and the mixture wasstirred at 80° C. for 12 h under N₂. LCMS showed the reaction wascomplete. The mixture was concentrated. The residue was purified byprep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1). tert-butyl(S)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(260 mg, crude) was obtained as a yellow oil.

Step 8:(S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)methanamine

A solution of tert-butyl(S)-4-(3-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 161 umol, 1.00 eq) in TFA (1.50 mL) and DCM (3.00 mL) wasstirred at 20° C. for 1 hr. The mixture was concentrated. The mixturewas purified by prep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um;mobile phase: [water (0.04% HCl)-ACN]; B %: 10%-45%, 10 min). Thefraction was blown to dryness by a nitrogen stream to remove most ofMeCN and the aqueous phase was lyophilized.(S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)methanamine(45.0 mg, 98.0 umol, 60% yield, 99.7% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.51 (s, 1H), 7.98-7.89 (m,1H), 6.93 (t, J=9.4 Hz, 1H), 6.70 (dd, J=8.6, 3.7 Hz, 1H), 6.61 (s, 1H),5.19 (br d, J=14.7 Hz, 1H), 4.99-4.93 (m, 1H), 4.80-4.71 (m, 1H), 4.63(t, J=9.4 Hz, 1H), 4.32 (br dd, J=9.6, 3.0 Hz, 1H), 4.19 (s, 2H),4.13-4.02 (m, 1H), 3.97-3.86 (m, 1H), 3.83 (s, 3H). LCMS (ESI+): m/z422.2 (M+H).

Example 99:(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylmethanamine

To a solution of(S)-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)methanamine(86.1 mg, 161 umol, 1.00 eq, TFA) in MeOH (3.00 mL) was added AcOH (96.6ug, 1.61 umol, 0.0920 mL, 0.0100 eq), formaldehyde (26.1 mg, 322 umol,23.9 uL, 2.00 eq) at 20° C. and stirred at 20° C. for 0.5 hr. NaBH₃CN(20.2 mg, 321 umol, 2.00 eq) was added to the solution at 20° C. andstirred at 20° C. for 1 hr. LCMS showed that the reaction was complete.The mixture was concentrated. The mixture was purified by prep-HPLC(column: Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 5%-35%, 10 min), the fraction was blown to dryness by anitrogen stream to remove most of MeCN and the aqueous phase waslyophilized.(S)-1-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylmethanamine(35.0 mg, 69.7 umol, 43% yield, 96.7% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.56 (s, 1H), 8.06 (s, 1H),6.94 (t, J=9.5 Hz, 1H), 6.74 (s, 1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 5.22(d, J=14.9 Hz, 1H), 4.98 (br d, J=15.0 Hz, 1H), 4.81-4.75 (m, 1H),4.68-4.59 (m, 1H), 4.39 (s, 2H), 4.33 (br dd, J=9.7, 3.2 Hz, 1H),4.12-4.03 (m, 1H), 3.98-3.89 (m, 1H), 3.85 (s, 3H), 2.96 (s, 6H). LCMS(ESI+): m/z 450.2 (M+H).

Example 100:(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-cyclopropyl-5-(trimethylstannyl)pyrimidine

A mixture of 5-bromo-4-cyclopropylpyrimidine (200 mg, 1.00 mmol, 1.00eq), trimethyl(trimethylstannyl)stannane (658 mg, 2.01 mmol, 417 uL,2.00 eq), Pd(PPh₃)₄ (116 mg, 100 umol, 0.100 eq) in dioxane (8.00 mL)was degassed and purged with nitrogen 3 times at 20° C., and the mixturewas stirred at 100° C. for 2 h under nitrogen atmosphere.4-cyclopropyl-5-(trimethylstannyl)pyrimidine (284 mg, 1.00 mmol, 99%yield) was obtained as yellow liquid in dioxane (8.00 mL), which wasused to the next step directly.

Step 2: tert-butyl(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(164 mg, 335 umol, 1.00 eq),4-cyclopropyl-5-(trimethylstannyl)pyrimidine (284 mg, 1.00 mmol, 3.00eq), LiCl (28.4 mg, 669 umol, 13.7 uL, 2.00 eq), CuI (25.5 mg, 134 umol,0.400 eq) and Pd(PPh₃)₄ (38.7 mg, 33.5 umol, 0.100 eq) in dioxane (8.00mL) was degassed and purged with nitrogen 3 times at 20° C., and thenthe mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. Thereaction mixture was diluted with water (3.00 mL) and extracted withEtOAc (3.00 mL*3). The combined organic layers were washed with brine(3.00 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, PE:EtOAc=3:1).tert-butyl(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 283 umol, 84% yield) was obtained as a yellow oil.

Step 3:(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To HFIP (4.00 mL) was added tert-butyl(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 283 umol, 1.00 eq) at 20° C., then the mixture was stirred at80° C. for 12 h. The mixture was concentrated. The mixture was purifiedby prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobilephase: [water (10 mM NH₄HCO₃)-ACN]; B %: 28%-48%, 10 min). 50.0 mg ofthe product was obtained, which was then purified by prep-HPLC (column:Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2%FA)-ACN]; B %: 10%-45%, 10 min).(S)-4-(4-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(33.6 mg, 77.4 umol, 27% yield, 99.2% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.44 (s, 1H), 8.97 (s, 1H), 8.65 (s,1H), 7.61 (br t, J=6.4 Hz, 1H), 7.45 (s, 1H), 7.02-6.92 (m, 1H), 6.70(dd, J=8.7, 3.9 Hz, 1H), 4.98-4.89 (m, 1H), 4.86-4.74 (m, 1H), 4.59-4.43(m, 2H), 4.21 (br dd, J=9.1, 3.4 Hz, 1H), 4.11-3.99 (m, 1H), 3.93-3.81(m, 1H), 2.00-1.87 (m, 1H), 1.10 (br d, J=3.5 Hz, 2H), 0.95 (br dd,J=7.6, 2.8 Hz, 2H). LCMS (ESI+): m/z 431.1 (M+H).

Example 101:(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-3-fluoro-2-methylpyridine (100 mg, 526 umol,1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(200 mg, 789 umol, 1.50 eq) in dioxane (4.00 mL) was added KOAc (103 mg,1.05 mmol, 2.00 eq), Pd(dppf)Cl₂ (38.5 mg, 52.6 umol, 0.100 eq) at 20°C., stirred at 100° C. for 2 h under N₂. The mixture was concentrated.3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(124 mg, crude) as obtained as black oil.

Step 2:(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(96.9 mg, 409 umol, 2.00 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(80.0 mg, 205 umol, 1.00 eq),4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (14.5mg, 20.5 umol, 14.5 uL, 0.100 eq) in EtOH (4.00 mL) and water (0.400 mL)was added KOAc (40.1 mg, 409 umol, 2.00 eq) at 20° C. and the reactionmixture was stirred at 100° C. for 12 h. The residue was dissolved inMeOH (3.00 mL) and silica-thiol (100 mg, modified silicon gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 3 h. The mixture was filtered, the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 20%-50%, 8 min). The fraction wasblown to dryness by a nitrogen stream to remove most of MeCN and theaqueous phase was lyophilized, then the product dissolved in MeOH (10.0mL) and water (3.00 mL). Aq. HCl (2.00 mL, 1.00 M) was added to thesolution which was then lyophilized.(S)-12-fluoro-4-(5-fluoro-6-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(23.8 mg, 50.1 umol, 24% yield, 96.3% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.63 (s, 1H), 8.96 (d, J=1.5Hz, 1H), 8.51 (dd, J=9.7, 1.2 Hz, 1H), 8.23 (s, 1H), 6.92 (dd, J=10.1,8.8 Hz, 1H), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 5.20 (d, J=14.7 Hz, 1H),5.01-4.96 (m, 1H), 4.87-4.78 (m, 1H), 4.68-4.59 (m, 1H), 4.35 (dd,J=9.7, 2.9 Hz, 1H), 4.12-3.95 (m, 2H), 2.76 (d, J=2.4 Hz, 3H). LCMS(ESI+): m/z 422.0 (M+H).

Example 102:(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole

To a solution of 5-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (300 mg,1.59 mmol, 1.00 eq) in DCM (3.00 mL) was added DAST (512 mg, 3.17 mmol,419 uL, 2.00 eq) at −78° C. The mixture was stirred at 20° C. for 12 h.The reaction mixture was quenched by addition of saturated aqueousNaHCO₃ (3.00 mL), concentrated under reduced pressure to remove DCM, andextracted with EtOAc (2.00 mL*3). The combined organic layers werewashed with brine (3.00 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give5-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (300 mg, crude) as ayellow oil.

Step 2: 3-(difluoromethyl)-1-methyl-5-(tributylstannyl)-1H-pyrazole

To a solution of 5-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole (290mg, 1.37 mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 715uL, 1.30 eq) at −78° C. under N₂. The mixture was stirred at −78° C. for0.5 hr. To the mixture was added tributyl(chloro)stannane (1.79 g, 5.50mmol, 1.48 mL, 4.00 eq) at −78° C. under N₂. The mixture was stirred at−78° C. for 2 h. LC-MS showed that5-bromo-3-(difluoromethyl)-1-methyl-1H-pyrazole was consumed completelyand the desired mass was detected. The reaction mixture was quenched byaddition of saturated aqueous NH₄Cl (5.00 mL). THF layer was separatedand the aqueous layer was extracted with EtOAc (3.00 mL*3). The combinedorganic layers were washed with brine (5.00 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford3-(difluoromethyl)-1-methyl-5-(tributylstannyl)-1H-pyrazole (570 mg,crude) as a yellow oil.

Step 3: tert-butyl(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 3-(difluoromethyl)-1-methyl-5-(tributylstannyl)-1H-pyrazole(560 mg, 1.33 mmol, 2.50 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(261 mg, 532 umol, 1.00 eq), Pd(PPh₃)₄ (61.5 mg, 53.2 umol, 0.100 eq),CuI (40.5 mg, 213 umol, 0.400 eq) and LiCl (45.1 mg, 1.06 mmol, 21.8 uL,2.00 eq) in dioxane (10.0 mL) was degassed and purged with nitrogen 3times at 20° C. The reaction mixture was stirred at 80° C. for 12 hunder nitrogen atmosphere. The mixture was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 0/1). tert-butyl(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(230 mg, crude) was obtained as a brown solid.

Step 4:(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To the HFIP (5.00 mL) was added tert-butyl(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 369 umol, 1.00 eq) at 20° C., the mixture was stirred at 100°C. for 12 h The reaction mixture was concentrated under reducedpressure. The mixture was dissolved in DMSO (5.00 mL). The mixture waspurified by neutral prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 35%-60%, 10 min). Thefraction was lyophilized. 70 mg of crude product was obtained anddissolved in DMSO (5.00 mL). The obtained sample was purified by acidicprep-HPLC. (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase:[water (0.2% FA)-ACN]; B %: 20%-60%, 10 min).(S)-4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(58.3 mg, 126 umol, 34% yield, 95.9% purity) was obtained bylyophilization as a white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.46 (s,1H), 7.75 (br t, J=6.2 Hz, 1H), 7.53 (s, 1H), 7.00 (t, J=54.8 Hz, 1H),6.99-6.93 (m, 1H), 6.82 (s, 1H), 6.70 (dd, J=8.7, 3.8 Hz, 1H), 4.96-4.88(m, 1H), 4.86-4.76 (m, 1H), 4.60-4.45 (m, 2H), 4.24-4.17 (m, 1H),4.10-3.98 (m, 1H), 3.93-3.88 (m, 1H), 3.87 (s, 3H). LCMS (ESI+): m/z443.1 (M+H).

Example 103:(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: (1,5-dimethyl-1H-imidazol-4-yl)boronic acid

To a solution of 4-bromo-1,5-dimethyl-1H-imidazole (800 mg, 4.57 mmol,1.00 eq) in THF (6.00 mL) was added n-BuLi (2.50 M, 3.66 mL, 2.00 eq) at0° C. under N₂. The mixture was stirred at 20° C. for 1 hr. Thentriisopropyl borate (2.58 g, 13.7 mmol, 3.15 mL, 3.00 eq) was added tothe mixture at 0° C. and stirred at 0° C. for 1 hr. The reaction mixturewas quenched by addition of MeOH (5.00 mL) at 0° C. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase:[water (0.2% FA)-ACN]; B %: 1%-20%, 10 min).(1,5-dimethyl-1H-imidazol-4-yl)boronic acid (450 mg, crude) was obtainedas yellow oil.

Step 2: tert-butyl(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(197 mg, 401 umol, 1.00 eq) in dioxane (5.00 mL) was added(1,5-dimethyl-1H-imidazol-4-yl)boronic acid (280 mg, 2.00 mmol, 5.00eq), Pd(dppf)Cl₂ DCM complex (65.3 mg, 80.0 umol, 0.200 eq), water(0.500 mL) and Na₂CO₃ (106 mg, 1.00 mmol, 2.98 uL, 2.50 eq) at 20° C.under N₂. The mixture was stirred at 80° C. for 12 h. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Ethyl acetate/MeOH=10/1). tert-butyl(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, crude) was obtained as a brown solid.

Step 3:(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 158 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C.for 3 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (column: Phenomenex Luna C18100*30 mm*5 um; mobile phase: [water (0.2% FA)-ACN]; B %: 10%-35%, 10min).(S)-4-(1,5-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(9.50 mg, 20.8 umol, 13% yield, 99.1% purity, formate salt) was obtainedas a white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.38 (br s, 1H), 7.63 (brs, 1H), 7.41-7.26 (m, 2H), 6.94 (t, J=9.6 Hz, 1H), 6.67 (dd, J=3.6, 8.8Hz, 1H), 4.88 (br dd, J=5.6, 15.1 Hz, 1H), 4.75 (br dd, J=6.8, 14.8 Hz,1H), 4.56-4.47 (m, 2H), 4.28-4.21 (m, 2H), 4.02 (br s, 1H), 3.90-3.78(m, 1H), 3.59 (s, 3H), 2.35 (s, 3H). LCMS (ESI+): m/z 407.16 (M+H).

Example 104:(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-bromo-1,2-dimethyl-1H-imidazole

To a solution of 5-bromo-2-methyl-1H-imidazole (2.00 g, 12.4 mmol, 1.00eq) and Mel (2.12 g, 14.9 mmol, 928 uL, 1.20 eq) in DMF (10.0 mL) wasadded K₂CO₃ (3.78 g, 27.3 mmol, 2.20 eq) at 20° C. The mixture wasstirred at 20° C. for 12 h. The reaction mixture was diluted with water(30.0 mL), extracted with ethyl acetate (15.0 mL*3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Ethyl acetate:Methanol=20:1).4-bromo-1,2-dimethyl-1H-imidazole (500 mg, 2.86 mmol, 23% yield) wasobtained as a white solid. ¹H NMR CD₃OD 400 MHz δ=ppm 6.97 (s, 1H), 3.58(s, 3H), 2.31 (s, 3H).

Step 2: tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 4-bromo-1,2-dimethyl-1H-imidazole (60.0 mg, 343 umol, 1.00eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Ex. 16; 241 mg, 344 umol, 1.00 eq), Pd(f-Bu₃P)₂ (17.6 mg, 34.4 umol,0.100 eq) in dioxane (1.00 mL) was degassed and purged with nitrogen 3times at 20° C., and the mixture was stirred at 100° C. for 2 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Ethylacetate/Methanol=5/1). tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 178 umol, 51% yield) was obtained as a yellow solid.

Step 3:(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 178 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80° C. for1 hr. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (HCl conditions). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(1,2-dimethyl-1H-imidazol-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(15.5 mg, 34.1 umol, 19% yield, 97.5% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.54 (s, 1H), 8.01 (s, 1H),7.99 (s, 1H), 6.88 (dd, J=10.1, 8.9 Hz, 1H), 6.64 (dd, J=8.7, 3.8 Hz,1H), 5.11 (d, J=14.7 Hz, 1H), 4.93 (br s, 1H), 4.74 (br d, J=6.0 Hz,1H), 4.60 (t, J=9.3 Hz, 1H), 4.31 (dd, J=9.7, 3.0 Hz, 1H), 4.09-3.99 (m,1H), 3.95 (br d, J=10.3 Hz, 1H), 3.89 (s, 3H), 2.73 (s, 3H). LCMS(ESI+): m/z 407.1 (M+H).

Example 105:(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-bromo-2-iodo-6-methylpyridine

To a solution of I₂ (5.43 g, 21.4 mmol, 4.31 mL, 2.00 eq), CuI (2.65 g,13.9 mmol, 1.30 eq), isopentyl nitrite (1.88 g, 16.0 mmol, 2.16 mL, 1.50eq) in MeCN (30.0 mL) was added 3-bromo-6-methylpyridin-2-amine (2.00 g,10.7 mmol, 1.00 eq) at 0° C. The mixture was stirred at 60° C. for 2 hThe reaction mixture was quenched by Na₂SO₃˜30.0 g at 20° C., and thenfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 10/1). 3-bromo-2-iodo-6-methylpyridine (1.60g, 5.37 mmol, 50% yield) was obtained as a yellow solid.

Step 2: 3-bromo-6-methyl-2-vinylpyridine

A mixture of 3-bromo-2-iodo-6-methylpyridine (1.60 g, 5.37 mmol, 1.00eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (744 mg, 4.83 mmol,820 uL, 0.900 eq), Na₂CO₃ (1.14 g, 10.7 mmol, 2.00 eq) and Pd(dppf)Cl₂(196 mg, 269 umol, 0.0500 eq) in dioxane (20.0 mL) and water (2.00 mL)was degassed and purged with nitrogen 3 times at 20° C., and the mixturewas stirred at 80° C. for 2 h under nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 10/1). 3-bromo-6-methyl-2-vinylpyridine (600 mg, 3.03mmol, 56% yield) was obtained as a yellow oil.

Step 3: 3-bromo-6-methylpicolinaldehyde

Ozone was bubbled into a solution of 3-bromo-6-methyl-2-vinylpyridine(600 mg, 3.03 mmol, 1.00 eq) in DCM (35.0 mL) at −78° C. for 0.5 hr.After excess O₃ was purged by O₂, Me₂S (2.82 g, 45.5 mmol, 3.34 mL, 15.0eq) was added to the mixture at 20° C. The mixture was stirred at 20° C.for 8 h. LC-MS showed 3-bromo-6-methyl-2-vinylpyridine was consumedcompletely and one main peak with desired mass was detected. The mixturewas concentrated and water (10.0 mL) was added to the solution. Themixture was extracted with EtOAc (10.0 mL*3), the combined organiclayers were dried over Na₂SO₄ and concentrated. The residue was purifiedby flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica FlashColumn, Eluent of 0-11% Ethyl acetate/Petroleum ether gradient @ 40mL/min). 3-bromo-6-methylpicolinaldehyde (250 mg, 1.25 mmol, 41% yield)was obtained as a white solid.

Step 4: 3-bromo-2-(difluoromethyl)-6-methylpyridine

To a solution of 3-bromo-6-methylpicolinaldehyde (250 mg, 1.25 mmol,1.00 eq) in DCM (4.00 mL) was added DAST (403 mg, 2.50 mmol, 330 uL,2.00 eq) at 0° C. The mixture was stirred at 20° C. for 10 h. Cold water(2.00 mL) was added to the solution, then the mixture was extracted withEtOAc (3.00 mL*3), the combined organic layers were dried over Na₂SO₄and concentrated. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=5/1). 3-bromo-2-(difluoromethyl)-6-methylpyridine(100 mg, 450 umol, 36% yield) was obtained as a yellow gum.

Step 5: tert-butyl(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 3-bromo-2-(difluoromethyl)-6-methylpyridine (70.0 mg, 315umol, 1.00 eq), tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(221 mg, 315 umol, 1.00 eq) and Pd(f-Bu₃P)₂ (16.1 mg, 31.5 umol, 0.100eq) in dioxane (1.00 mL) was degassed and purged with nitrogen 3 timesat 20° C., and the mixture was stirred at 100° C. for 10 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=1/3). tert-butyl(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 145 umol, 45% yield) was obtained as a yellow solid.

Step 6:(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 145 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 80° C. for5 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC (HClconditions). ¹H NMR indicated insufficient purity. The product wasfurther purified by prep-HPLC (formic acid conditions). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-4-(2-(difluoromethyl)-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(18.0 mg, 38.0 umol, 26% yield, 95.6% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (s, 1H), 7.90 (d, J=7.9 Hz,1H), 7.59 (br t, J=6.3 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (s, 1H),6.96 (br t, J=9.6 Hz, 1H), 6.83 (t, J=54.8 Hz, 1H), 6.72-6.65 (m, 1H),4.96-4.86 (m, 1H), 4.82-4.71 (m, 1H), 4.52 (br t, J=9.4 Hz, 1H), 4.44(br s, 1H), 4.19 (br dd, J=9.5, 3.5 Hz, 1H), 4.02 (br s, 1H), 3.91-3.79(m, 1H), 2.57 (s, 3H). LCMS (ESI+): m/z 454.1 (M+H).

Example 106:(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-methyl-2-(tributylstannyl)pyridine

To a solution of 2-bromo-5-methylpyridine (1.00 g, 5.81 mmol, 1.00 eq)in THF (10.0 mL) was added n-BuLi (2.50 M, 2.81 mL, 1.21 eq) at −70° C.under N₂. The mixture was stirred at −70° C. for 0.5 hr.Tributyl(chloro)stannane (2.84 g, 8.72 mmol, 2.35 mL, 1.50 eq) was addedto the mixture at −70° C. and the mixture was stirred at 0° C. for 1 hrThe reaction mixture was quenched by addition of water (10.0 mL) at 20°C., and extracted with PE (15.0 mL*3). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 20/1). 5-methyl-2-(tributylstannyl)pyridine(500 mg, crude) was obtained as a yellow liquid.

Step 2: tert-butyl(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq) in dioxane (6.00 mL) was added5-methyl-2-(tributylstannyl)pyridine (311 mg, 814 umol, 2.00 eq),Pd(PPh₃)₄ (47.0 mg, 40.7 umol, 9.99e-2 eq) and LiCl (40.0 mg, 944 umol,19.3 uL, 2.32 eq), CuI (30.0 mg, 158 umol, 3.87e-1 eq) at 20° C. underN₂. The mixture was stirred at 100° C. for 12 h. The reaction mixturewas concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/3). tert-butyl(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, crude) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 199 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C. for2 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.04% HCl)-ACN]; B %: 10% 35%, 10min).(S)-12-fluoro-4-(5-methylpyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(38.0 mg, 84.1 umol, 42% yield, 97.3% purity, HCl) was obtained as abrown solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.65 (br s, 1H), 8.67 (s, 1H),8.58 (s, 1H), 8.26 (br s, 1H), 8.10 (br s, 1H), 6.91 (br t, J=9.4 Hz,1H), 6.67 (br dd, J=8.4, 3.0 Hz, 1H), 5.18 (br s, 1H), 5.07-4.99 (m,1H), 4.81 (br s, 1H), 4.64 (br t, J=8.9 Hz, 1H), 4.33 (br d, J=9.2 Hz,1H), 4.07 (br s, 2H), 2.51 (br s, 3H). ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.93(br s, 1H), 8.96 (br s, 1H), 8.66 (br s, 2H), 8.44 (br s, 1H), 8.02 (brs, 1H), 7.09-6.94 (m, 1H), 6.74 (br d, J=6.0 Hz, 1H), 4.95 (br s, 2H),4.57 (br d, J=9.2 Hz, 2H), 4.24 (br d, J=7.2 Hz, 1H), 4.11 (br s, 1H),4.00-3.95 (m, 1H), 2.40 (s, 3H). LCMS (ESI+): m/z 404.0 (M+H).

Example 107:(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1:3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To 5-bromo-3-chloro-2-methylpyridine (150 mg, 727 umol, 1.00 eq) indioxane (5.00 mL) were added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(369 mg, 1.45 mmol, 2.00 eq), Pd(dppf)Cl₂ (53.2 mg, 72.7 umol, 0.100eq), KOAc (143 mg, 1.45 mmol, 2.00 eq) at 20° C. Then the mixture wasstirred at 100° C. for 2 h under nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure to give3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(200 mg, crude) as brown solid.

Step 2: tert-butyl(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(155 mg, 611 umol, 2.00 eq) in EtOH (3.00 mL) and water (0.600 mL) wasadded KOAc (89.9 mg, 916 umol, 3.00 eq),4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (21.6mg, 30.5 umol, 21.6 uL, 0.100 eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq) at 20° C. The mixture was stirred at 80° C.for 2 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,PE:EtOAc=0:1). tert-butyl(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, crude) was obtained as yellow solid.

Step 3:(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 223 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C. Themixture was stirred at 100° C. for 12 h. LC-MS showed tert-butyl(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was concentrated under reduced pressure.The crude product was purified by prep-HPLC (HCl conditions).(S)-4-(5-chloro-6-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(30.4 mg, 68.8 umol, 30% yield, 99.1% purity) was obtained as yellowsolid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.81 (s, 1H), 9.09 (s, 1H), 8.97 (s,1H), 8.33 (s, 1H), 6.90 (t, J=9.4 Hz, 1H), 6.66 (dd, J=8.5, 3.6 Hz, 1H),5.19 (d, J=14.8 Hz, 1H), 5.09-4.93 (m, 1H), 4.89-4.76 (m, 1H), 4.62 (t,J=9.2 Hz, 1H), 4.42-4.28 (m, 1H), 4.19-3.90 (m, 2H), 2.93 (s, 3H). LCMS(ESI+): m/z 438.1/440.0 (M+H)/(M+3).

Example 108:(S)-12-fluoro-4-(2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(90.0 mg, 230 umol, 1.00 eq), (2-methyl-4-pyridyl)boronic acid (47.3 mg,345 umol, 1.50 eq), 4-ditert-butylphosphanyl-N,N-dimethyl-anilinedichloropalladium (16.3 mg, 23.0 umol, 16.3 uL, 0.100 eq), KOAc (45.0mg, 459 umol, 1.99 eq) in EtOH (5.00 mL) and water (0.500 mL) wasdegassed and purged with nitrogen 3 times and the mixture was stirred at80° C. for 8 hr under nitrogen atmosphere. The residue was dissolved inMeOH (5.00 mL) and silica-thiol (200 mg, modified silicon gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 3 h. The suspension was filtered, the filtrate wasconcentrated and purified by acidic prep-HPLC (column: Phenomenex LunaC18 150*30 mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B %: 15%-40%,10 min). The product-containing fraction was concentrated under reducedpressure to remove most of MeCN at 30° C. and the aqueous phase waslyophilized.(S)-12-fluoro-4-(2-methylpyridin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(54.3 mg, 123 umol, 53% yield, 99.4% purity, HCl salt) was obtained asan orange solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.61 (s, 1H), 8.68 (d, J=6.4Hz, 1H), 8.49 (s, 1H), 8.44 (br d, J=6.2 Hz, 1H), 8.40 (s, 1H), 6.90 (t,J=9.4 Hz, 1H), 6.66 (dd, J=8.7, 3.9 Hz, 1H), 5.21 (br d, J=14.8 Hz, 1H),4.98 (br d, J=14.6 Hz, 1H), 4.80 (br s, 1H), 4.62 (br t, J=9.2 Hz, 1H),4.32 (br d, J=7.7 Hz, 1H), 4.14-3.91 (m, 2H), 2.83 (s, 3H). LCMS (ESI+):m/z 404.2 (M+H).

Example 109:(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-methoxy-2-(trimethylstannyl)pyridine

To a solution of 2-bromo-3-methoxypyridine (400 mg, 2.13 mmol, 1.00 eq)in dioxane (6.00 mL) was added Pd(PPh₃)₄ (246 mg, 213 umol, 0.100 eq)and trimethyl(trimethylstannyl)stannane (1.39 g, 4.25 mmol, 882 uL, 2.00eq) at 20° C. under N₂. The mixture was stirred at 100° C. for 2 h.LC-MS showed no 2-bromo-3-methoxypyridine was remained. Several newpeaks were shown on LC-MS and desired m/s was detected. The reactionmixture was filtered and the filtrate was collected.3-methoxy-2-(trimethylstannyl)pyridine (578 mg, crude) was dissolved indioxane (6.00 mL) and used into next step directly.

Step 2: tert-butyl(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq) in dioxane (2.00 mL) was added3-methoxy-2-(trimethylstannyl)pyridine (578 mg, 2.13 mmol, 5.22 eq) indioxane (6.00 mL), Pd(PPh₃)₄ (47.0 mg, 40.7 umol, 0.100 eq), CuI (38.8mg, 204 umol, 0.500 eq) and LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq)at 20° C. under N₂. The mixture was stirred at 100° C. for 2 h. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-butyl(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(85.0 mg, crude) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(85.0 mg, 164 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C.for 2 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*30 mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B %: 20%-50%, 10min).(S)-12-fluoro-4-(3-methoxypyridin-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(23.0 mg, 48.9 umol, 29% yield, 97.0% purity, HCl salt) was obtained asa yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 10.13 (s, 1H), 9.18 (br t,J=6.0 Hz, 1H), 8.66 (s, 1H), 8.42-8.34 (m, 1H), 7.80-7.71 (m, 1H), 7.50(dd, J=8.4, 4.8 Hz, 1H), 7.02 (t, J=9.6 Hz, 1H), 6.75 (dd, J=8.4, 4.0Hz, 1H), 5.06-4.92 (m, 2H), 4.54 (br t, J=9.2 Hz, 2H), 4.29-4.22 (m,1H), 4.16 (br s, 1H), 4.00 (br s, 1H), 3.99 (s, 3H). LCMS (ESI+): m/z420.0 (M+H).

Example 110:(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 285 umol, 1.00 eq) in dioxane (6.00 mL) was added4-(tributylstannyl)pyrimidine (210 mg, 569 umol, 2.00 eq), Pd(PPh₃)₄(32.9 mg, 28.5 umol, 0.100 eq), LiCl (24.2 mg, 571 umol, 11.7 uL, 2.00eq) and CuI (21.7 mg, 114 umol, 0.400 eq) at 20° C. The mixture wasstirred at 100° C. for 12 h under nitrogen atmosphere. The reaction wasconcentrated. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=0/1). tert-butyl(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, crude) was obtained as a green solid.

Step 2: Example 151:(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 285 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100° C. for12 h The reaction was concentrated. The residue was dissolved in DMSO(4.00 mL), the mixture was purified by acidic prep-HPLC (column:Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 25%-40%, 10 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-12-fluoro-4-(pyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(36.2 mg, 84.8 umol, 29% yield, 100% purity, HCl salt) was obtained asan orange solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.95 (s, 1H), 9.22 (s,1H), 9.01 (br s, 1H), 8.88 (br d, J=5.3 Hz, 1H), 8.67 (s, 2H), 6.98 (brt, J=9.5 Hz, 1H), 6.71 (dd, J=8.6, 3.5 Hz, 1H), 5.17-4.91 (m, 2H),4.69-4.51 (m, 2H), 4.24 (dd, J=9.2, 4.1 Hz, 1H), 4.17-4.09 (m, 1H),4.05-3.96 (m, 1H). LCMS (ESI+): m/z 391.1 (M+H).

Example 111:(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-methyl-6-(trimethylstannyl)pyrimidine

To 4-bromo-6-methylpyrimidine (200 mg, 1.16 mmol, 1.00 eq) in dioxane(4.00 mL) was added trimethyl(trimethylstannyl)stannane (757 mg, 2.31mmol, 479 uL, 2.00 eq) and Pd(PPh₃)₄ (134 mg, 116 umol, 0.100 eq) at 20°C. The mixture was stirred at 100° C. for 12 h under nitrogenatmosphere. LC-MS showed 4-bromo-6-methylpyrimidine was consumedcompletely and one main peak with desired mass was detected. Theobtained solution of 4-methyl-6-(trimethylstannyl)pyrimidine (297 mg,crude) was used in next step directly.

Step 2: tert-butyl(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To 4-methyl-6-(trimethylstannyl)pyrimidine (297 mg, 1.16 mmol, 2.84 eq)in dioxane (4.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq), CuI (31.0 mg, 163 umol, 0.400 eq), LiCl(34.5 mg, 814 umol, 16.7 uL, 2.00 eq) and Pd(PPh₃)₄ (47.0 mg, 40.7 umol,0.100 eq) at 20° C. The mixture was stirred at 80° C. for 2 h undernitrogen atmosphere. The reaction mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=1:1). tert-butyl(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, crude) was obtained as brown oil.

Step 3:(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, 357 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C. Themixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The crude product was purified byprep-HPLC (HCl conditions).(S)-12-fluoro-4-(6-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(24.9 mg, 55.9 umol, 15% yield, 98.9% purity, HCl salt) was obtained asyellow solid. ¹H NMR CD₃OD 400 MHz. δ=ppm 9.60 (s, 1H), 9.26 (s, 1H),8.89 (s, 1H), 8.41 (s, 1H), 6.94 (t, J=9.2 Hz, 1H), 6.76-6.66 (m, 1H),5.35-5.27 (m, 1H), 5.03 (br s, 2H), 4.70-4.60 (m, 1H), 4.42-4.28 (m,1H), 4.19-3.95 (m, 2H), 2.74 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).

Example 112:(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-ethyl-1-methyl-1H-pyrazol-5-ol

A mixture of methyl 3-oxopentanoate (5.00 g, 38.4 mmol, 4.76 mL, 1.00eq), methylhydrazine (1.86 g, 16.2 mmol, 2.13 mL, 0.420 eq), HCl (12.0M, 160 uL, 0.0500 eq) in EtOH (100 mL) was degassed and purged withnitrogen 3 times at 20° C., and the mixture was stirred at 80° C. for 10h under nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure. The residue was purified by flash silica gelchromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of0-20% Ethylacetate/Petroleum ether gradient @ 50 mL/min).3-Ethyl-1-methyl-1H-pyrazol-5-ol (1.90 g, 15.1 mmol, 39% yield) wasobtained as a light red solid. ¹H NMR DMSO-d₆ 400 MHz 3=ppm 10.67 (br s,1H), 5.11 (s, 1H), 3.37 (br s, 3H), 2.34 (q, J=7.6 Hz, 2H), 1.06 (t,J=7.6 Hz, 3H).

Step 2: 3-ethyl-1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate

To a solution of 3-ethyl-1-methyl-1H-pyrazol-5-ol (500 mg, 3.96 mmol,1.00 eq),1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(1.70 g, 4.76 mmol, 1.20 eq) in DCM (10.0 mL) was added DIPEA (1.02 g,7.93 mmol, 1.38 mL, 2.00 eq) at 0° C. The mixture was stirred at 20° C.for 10 h. The reaction mixture was concentrated under reduced pressure.The residue was purified by flash silica gel chromatography (ISCO®; 12 gSepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleumether gradient @ 30 mL/min). 3-ethyl-1-methyl-1H-pyrazol-5-yltrifluoromethanesulfonate (700 mg, 2.71 mmol, 68% yield) was obtained asa colourless oil.

Step 3:3-ethyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 3-ethyl-1-methyl-1H-pyrazol-5-yl trifluoromethanesulfonate(500 mg, 1.94 mmol, 1.00 eq),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(740 mg, 2.91 mmol, 1.50 eq), KOAc (570 mg, 5.81 mmol, 3.00 eq),Pd(dppf)Cl₂ (142 mg, 194 umol, 0.100 eq) in dioxane (15.0 mL) wasdegassed and purged with nitrogen 3 times at 20° C., and the mixture wasstirred at 90° C. for 10 h under nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/1).3-ethyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(260 mg, 1.10 mmol, 56% yield) was obtained as a light yellow solid.

Step 4: tert-butyl(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of3-ethyl-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(127 mg, 538 umol, 1.20 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(220 mg, 448 umol, 1.00 eq), Na₂CO₃ (94.9 mg, 895 umol, 2.00 eq),Pd(dppf)Cl₂ (32.8 mg, 44.8 umol, 0.100 eq) in dioxane (5.00 mL) andwater (0.500 mL) was degassed and purged with nitrogen 3 times at 20°C., and the mixture was stirred at 80° C. for 10 h under nitrogenatmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=0/1). tert-butyl(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 211 umol, 47% yield) was obtained as a brown solid.

Step 5:(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 211 umol, 1.00 eq) in DCM (2.50 mL) was added TFA (1.00 mL) at20° C. The mixture was stirred at 20° C. for 1 hr. The reaction mixtureconcentrated under reduced pressure. The residue was purified byprep-HPLC (HCl condition). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(3-ethyl-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(36.6 mg, 79.9 umol, 37% yield, 99.8% purity, HCl) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.56 (s, 1H), 8.07 (s, 1H),6.93 (dd, J=10.0, 8.8 Hz, 1H), 6.69 (dd, J=8.7, 3.9 Hz, 1H), 6.54 (s,1H), 5.22 (d, J=14.8 Hz, 1H), 4.97 (br d, J=14.7 Hz, 1H), 4.83-4.72 (m,1H), 4.63 (t, J=9.5 Hz, 1H), 4.32 (dd, J=9.7, 3.4 Hz, 1H), 4.12-4.00 (m,1H), 3.97-3.86 (m, 1H), 3.81 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 1.33 (t,J=7.6 Hz, 3H). LCMS (ESI+): m/z 421.1 (M+H).

Example 113:(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-chloro-4-iodopyrimidine

To a solution of 5-chloropyrimidin-4-amine (760 mg, 5.87 mmol, 1.00 eq)and CH₂I₂ (3.14 g, 11.7 mmol, 946 uL, 2.00 eq) in MeCN (15.0 mL) wasadded isopentyl nitrite (1.51 g, 12.9 mmol, 1.74 mL, 2.20 eq) in MeCN(3.00 mL) under nitrogen atmosphere at 0° C. The mixture was stirred at0° C. for 3 h. Then the mixture was stirred at 60° C. for 36 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=9/1). 5-Chloro-4-iodopyrimidine (570 mg,2.37 mmol, 40% yield) was obtained as a light yellow solid.

Step 2: tert-butyl(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq), 5-chloro-4-iodopyrimidine (137 mg, 570umol, 2.00 eq), Pd(f-Bu₃P)₂ (14.6 mg, 28.6 umol, 0.100 eq) in dioxane(5.00 mL) was degassed and purged with nitrogen 3 times, and the mixturewas stirred at 100° C. for 16 h under nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/3).tert-butyl(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(125 mg, crude) was obtained as a yellow oil.

Step 3:(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(125 mg, 238 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100° C. for12 hr under nitrogen atmosphere. LC-MS indicated low conversion. Themixture was concentrated under reduced pressure. The residue wasdissolved in DCM (5.00 mL) and TFA (2.00 mL) at 25° C. under nitrogenatmosphere, and the mixture was stirred at 25° C. for 1 hr. LC-MS showedthat the reaction was complete. The mixture was concentrated underreduced pressure. The residue was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 10%-30%, 10 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(5-chloropyrimidin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(22.0 mg, 46.9 umol, 19% yield, 98.3% purity, HCl) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.65 (s, 1H), 9.20 (s, 1H),8.98 (s, 1H), 8.95 (s, 1H), 6.95 (br t, J=9.5 Hz, 1H), 6.71 (dd, J=8.6,3.8 Hz, 1H), 5.28 (br d, J=14.7 Hz, 1H), 5.05 (br d, J=14.7 Hz, 2H),4.65 (br t, J=9.4 Hz, 1H), 4.35 (br d, J=7.2 Hz, 1H), 4.12 (br s, 1H),3.98 (br s, 1H). LCMS (ESI+): m/z 425.0/427.0 (M+H)/(M+3).

Example 114:(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-fluoro-4-iodopyrimidine

To a solution of 5-fluoropyrimidin-4-amine (250 mg, 2.21 mmol, 1.00 eq)and CH₂I₂ (1.18 g, 4.42 mmol, 357 uL, 2.00 eq) in MeCN (2.00 mL) wasadded isopentyl nitrite (570 mg, 4.87 mmol, 655 uL, 2.20 eq) in MeCN(0.500 mL) at 0° C. The mixture was stirred at 0° C. for 1 hr. Then themixture was warmed to 60° C. The mixture was stirred at 60° C. for 1 hr.The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=10/1). 5-fluoro-4-iodopyrimidine (80.0 mg, 357 umol, 16% yield)was obtained as a yellow solid.

Step 2: 5-fluoro-4-(trimethylstannyl)pyrimidine

A mixture of 5-fluoro-4-iodopyrimidine (80.0 mg, 357 umol, 1.00 eq),trimethyl(trimethylstannyl)stannane (234 mg, 715 umol, 148 uL, 2.00 eq)and Pd(PPh₃)₄ (41.3 mg, 35.7 umol, 0.100 eq) in dioxane (3.00 mL) wasdegassed and purged with nitrogen 3 times at 20° C., and the mixture wasstirred at 100° C. for 1 hr under nitrogen atmosphere. LC-MS showed5-fluoro-4-iodopyrimidine was consumed completely and one main peak withdesired mass was detected. 5-fluoro-4-(trimethylstannyl)pyrimidine (93.2mg, crude) in 3.00 mL of dioxane was used in the next step directly.

Step 3: tert-butyl(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 5-fluoro-4-(trimethylstannyl)pyrimidine (93.2 mg, 357 umol,1.00 eq) in dioxane (3.00 mL), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(176 mg, 358 umol, 1.00 eq), LiCl (22.7 mg, 535 umol, 11.0 uL, 1.50 eq),CuI (34.0 mg, 179 umol, 0.500 eq) and Pd(PPh₃)₄ (41.3 mg, 35.7 umol,0.100 eq) in dioxane (1.00 mL) was degassed and purged with nitrogen for3 times at 20° C., and the mixture was stirred at 100° C. for 12 h undernitrogen atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Ethylacetate/Methanol=10/1). tert-butyl(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, crude) was obtained as a yellow solid.

Step 4:(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(75.0 mg, 148 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 80° C. for10 h under nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure. The residue was purified by prep-HPLC (HClcondition). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-12-fluoro-4-(5-fluoropyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(19.6 mg, 43.7 umol, 29% yield, 99.2% purity, HCl) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.62 (s, 1H), 9.14 (d, J=2.9Hz, 1H), 8.88 (d, J=4.4 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 6.95 (dd,7=10.3, 8.8 Hz, 1H), 6.71 (dd, 7=8.8, 3.9 Hz, 1H), 5.36-5.24 (m, 1H),5.13-4.94 (m, 2H), 4.70-4.58 (m, 1H), 4.43-4.30 (m, 1H), 4.17-4.09 (m,1H), 4.06-3.89 (m, 1H). LCMS (ESI+): m/z 409.0 (M+H).

Example 115:(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-bromo-1,4-dimethyl-1H-imidazole

To a solution of NaH (745 mg, 18.6 mmol, 60% purity, 1.20 eq) in THF(12.5 mL) was added 5-bromo-4-methyl-1H-imidazole (2.50 g, 15.5 mmol,1.00 eq) in THF (12.5 mL) at 0° C., and the mixture was stirred at 20°C. for 0.5 hr. To the reaction mixture was added Mel (3.31 g, 23.3 mmol,1.45 mL, 1.50 eq) dropwise at 20° C. The mixture was stirred at 20° C.for 16 hr. The reaction mixture was quenched by addition of water (10.0mL) and extracted with EtOAc (20.0 mL*5). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether:Ethyl acetate=0:1). 5-Bromo-1,4-dimethyl-1H-imidazole (540 mg,3.09 mmol, 19% yield) was obtained as a light-yellow oil. ¹H NMR CDCl₃400 MHz δ=ppm 7.47 (s, 1H), 3.57 (s, 3H), 2.19 (s, 3H).

Step 2: tert-butyl(S)-4-(l,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in two batches. A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 143 umol, 1.10 eq), 5-bromo-1,4-dimethyl-1H-imidazole (68.0 mg,389 umol, 3.00 eq), Pd(f-Bu₃P)₂ (13.3 mg, 26.0 umol, 0.201 eq) indioxane (5.00 mL) was degassed and purged with nitrogen 3 times, and themixture was stirred at 100° C. for 16 h under nitrogen atmosphere. Thebatches we combined and concentrated under reduced pressure. The residuewas dissolved in MeOH (5.00 mL) and silica-thiol (300 mg, modifiedsilicon gel for eliminating Pd, irregular silica gel, 100-200 mesh,Chlorides (Cl), %≤0.004, particle size distribution 45-75 um) was addedat 20° C. and stirred at 20° C. for 3 h. The suspension was filtered,the filtrate was concentrated and purified by prep-HPLC (column: WelchXtimate C18 150*25 mm*5 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 40%-65%, 10 min). The product-containing fraction was concentratedunder reduced pressure to remove most of MeCN at 30° C. and the aqueousphase was lyophilized. tert-butyl(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(13 mg, 25.7 umol, 9% yield) was obtained as a colorless oil.

Step 3:(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(13.0 mg, 25.7 umol, 1.00 eq) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.00mL) was degassed and purged with nitrogen 3 times, and the mixture wasstirred at 100° C. for 36 hr under nitrogen atmosphere. The mixture wasconcentrated under reduced pressure. The residue was dissolved in DCM(2.00 mL) and TFA (1.54 g, 13.5 mmol, 1.00 mL, 526 eq) was addeddropwise at 20° C. The mixture was stirred at 20° C. for 1 hr. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.04% HCl)-ACN]; B %: 1%-20%, 10 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized. Theobtained product was combined with another batch of 5 mg. ¹H NMRindicated insufficient purity. The product was purified by prep-HPLC(column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 15%-45%, 10 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(1,4-dimethyl-1H-imidazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(10.1 mg, 22.7 umol, 88% yield, 99.6% purity, HCl salt) was obtained asa white solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.57 (s, 1H), 9.05 (s, 1H),8.10 (s, 1H), 6.93 (t, J=9.4 Hz, 1H), 6.69 (dd, J=8.4, 3.7 Hz, 1H), 5.23(br d, J=14.6 Hz, 1H), 4.97 (br d, J=15.0 Hz, 1H), 4.79 (br s, 1H), 4.63(br t, J=9.3 Hz, 1H), 4.31 (br d, J=6.8 Hz, 1H), 4.07 (br s, 1H), 3.92(br d, J=10.6 Hz, 1H), 3.70 (br s, 3H), 2.24 (br s, 3H). LCMS (ESI+):m/z 407.0 (M+H).

Example 116:(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-bromo-1,5-dimethyl-1H-imidazole

Two parallel reactions were set up. To a solution of2-bromo-5-methyl-1H-imidazole (600 mg, 3.73 mmol, 1.00 eq) in THF (8.00mL) was added NaH (298 mg, 7.45 mmol, 60% purity, 2.00 eq) at 0° C. Themixture was stirred at 0° C. for 0.5 hr under nitrogen atmosphere. Mel(1.06 g, 7.45 mmol, 464 uL, 2.00 eq) was added to the mixture at 0° C.and the mixture was stirred at 20° C. for 12 h under nitrogenatmosphere. LCMS showed 2-bromo-5-methyl-1H-imidazole was consumedcompletely and the desired mass was detected. TLC (SiO₂, Petroleumether/Ethyl acetate=1/1) showed two new spots formed. The batches werecombined, water (10.0 mL) was added, and the mixture was extracted withethyl acetate (10.0 mL*3). The combined organic layers were dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to0/1). 2-Bromo-1,5-dimethyl-1H-imidazole (450 mg, 2.57 mmol, 34% yield)was obtained as a yellow oil.

Step 2: tert-butyl(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq) in dioxane (8.00 mL) was added2-bromo-1,5-dimethyl-1H-imidazole (99.8 mg, 570 umol, 2.00 eq), CuI(21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 570 umol, 11.7 uL, 2.00eq) and Pd(PPh₃)₄ (33.0 mg, 28.5 umol, 0.100 eq) at 20° C. The mixturewas stirred at 100° C. for 12 h under nitrogen atmosphere. The reactionmixture was concentrated. The residue was dissolved in DMSO (7.00 mL)and purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um;mobile phase: [water (0.2% FA)-ACN]; B %: 25%-45%, 10 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.tert-Butyl(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 253 umol, 88% yield, formate salt) was obtained as a greensolid.

Step 3:(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 253 umol, 1.00 eq, FA) in HFIP (8.00 mL) was stirred at 100° C.for 6 h. The reaction was concentrated. The residue was dissolved inDMSO (5.00 mL). The suspension was filtered, the filtrate wasconcentrated and purified by acidic prep-HPLC (column: Waters XbridgePrep OBD C18 150*40 mm*10 um; mobile phase: [water (0.04% NH₃H₂O+10 mMNH₄HCO₃)-ACN]; B %: 15%-55%, 10 min). The product-containing fractionwas concentrated under reduced pressure to remove most of MeCN at 30° C.and the aqueous phase was lyophilized. The obtained product wasdissolved in water (2.00 mL), then HCl (12.0 M, 0.0100 mL) was added tothe mixture, and the solution was re-lyophilized.(S)-4-(1,5-dimethyl-1H-imidazol-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(17.1 mg, 38.4 umol, 15% yield, 99.4% purity, HCl salt) was obtained asagreen solid. ¹H NMR CD₃OD+1 drop HCl in D₂O 400 MHz δ=ppm 9.80 (s, 1H),8.36 (s, 1H), 7.57 (s, 1H), 7.05-6.86 (m, 1H), 6.71 (dd, J=8.7, 3.9 Hz,1H), 5.27 (br d, J=14.8 Hz, 1H), 5.09 (br s, 1H), 4.81 (br s, 1H), 4.65(t, J=9.5 Hz, 1H), 4.33 (br d, J=6.7 Hz, 1H), 4.15 (br s, 1H), 3.99 (brs, 1H), 3.74 (s, 3H), 2.49 (s, 3H). LCMS (ESI+): m/z 407.1 (M+H).

Example 117:(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-methyl-4-(trimethylstannyl)pyrimidine

To a solution of 4-bromo-2-methylpyrimidine (250 mg, 1.44 mmol, 1.00 eq)in dioxane (8.00 mL) was added trimethyl(trimethylstannyl)stannane (946mg, 2.89 mmol, 599 uL, 2.00 eq) and Pd(PPh₃)₄ (167 mg, 145 umol, 0.100eq) at 20° C. under N₂. The mixture was stirred at 100° C. for 3 h.LC-MS showed the 4-bromo-2-methylpyrimidine was consumed completely andthe desired mass was detected. The obtained solution of2-methyl-4-(trimethylstannyl)pyrimidine was used in the next stepdirectly.

Step 2: tert-butyl(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 2-methyl-4-(trimethylstannyl)pyrimidine (157 mg, 611umol, 2.00 eq) in dioxane (8.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), Pd(PPh₃)₄ (35.3 mg, 30.6 umol, 0.100 eq),CuI (23.3 mg, 122 umol, 0.400 eq) and LiCl (25.9 mg, 611 umol, 12.5 uL,2.00 eq) at 20° C. under N₂. The mixture was stirred at 100° C. for 12h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, Petroleum ether:Ethylacetate=0:1). tert-Butyl(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(154 mg, crude) was obtained as a brown oil.

Step 3:(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To the HFIP (2.00 mL) was added tert-butyl(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(154 mg, 305 umol, 1.00 eq) at 20° C. The mixture was stirred at 100° C.for 12 h. The reaction mixture was concentrated under reduced pressure.The residue was dissolved in DMSO (5.00 mL). The suspension was purifiedby neutral prep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 um;mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 20%-50%, 8 min). Theproduct was isolated by lyophilization. The product (30.0 mg) wasobtained as a yellow solid with insufficient purity. The material wasdissolved in DMSO (5.00 mL). The suspension was purified twice by acidicprep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 25%-37%, 10 min). The product-containingfraction was lyophilized.(S)-12-fluoro-4-(2-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(21.1 mg, 46.9 umol, 15% yield, 97.9% purity, HCl alt) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.63 (s, 1H), 8.92 (s, 1H),8.87 (d, J=6.6 Hz, 1H), 8.45 (d, J=6.6 Hz, 1H), 6.94 (t, J=9.5 Hz, 1H),6.71 (dd, J=8.7, 3.8 Hz, 1H), 5.33 (br d, J=14.4 Hz, 1H), 5.04 (br s,2H), 4.66 (br t, J=9.2 Hz, 1H), 4.36 (br s, 1H), 4.11 (br s, 1H),4.06-3.91 (m, 1H), 2.99 (s, 3H). LCMS (ESI+): m/z 405.0 (M+H).

Example 118:(S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-chloro-2-(tributylstannyl)pyridine

To a solution of 2-bromo-3-chloropyridine (6.00 g, 31.2 mmol, 1.00 eq)in THF (50.0 mL) was added n-BuLi (2.50 M, 13.7 mL, 1.10 eq) at −78° C.under nitrogen and the mixture was stirred at −78° C. for 0.5 hr.Tributyl(chloro)stannane (20.3 g, 62.4 mmol, 16.8 mL, 2.00 eq) was addedto the mixture under nitrogen atmosphere at −78° C. and the resultingmixture was stirred at −78° C. for 1.5 h under N₂. The mixture wasquenched with saturated aqueous NH₄Cl solution (30.0 mL) and the mixturewas extracted with EtOAc (30.0 mL*3). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The mixturewas purified by MPLC (SiO₂, PE/EtOAc=1/0 to 3/1) to give the crudeproduct. The crude product was purified by neutral prep-HPLC.3-Chloro-2-(tributylstannyl)pyridine (80.0 mg, 199 umol, 6.37e-1% yield)was obtained as yellow oil.

Step 2: tert-butyl(S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of 3-chloro-2-(tributylstannyl)pyridine (73.8 mg,183 umol, 1.00 eq) in dioxane (2.00 mL) was added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 183 umol, 1.00 eq), CuI (14.0 mg, 73.3 umol, 0.400 eq), LiCl(15.5 mg, 366 umol, 7.50 uL, 2.00 eq) and Pd(PPh₃)₄ (21.2 mg, 18.3 umol,0.100 eq) at 25° C. under N₂. The resulting mixture was stirred at 80°C. for 12 h. The mixture was concentrated under reduced pressure. Themixture was purified by prep-TLC (SiO₂, PE/EtOAc=0/1). tert-butyl(S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 172 umol, 93% yield) was obtained as yellow oil.

Step 3:(S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(3-chloropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 172 umol, 1.00 eq) was added HFIP (2.00 mL) at 25° C. and themixture was stirred at 80° C. for 12 h. The mixture was concentratedunder reduced pressure. The mixture was purified by acidic prep-HPLC(HCl).(S)-4-(3-Chloropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(25.3 mg, 53.7 umol, 31% yield, 97.7% purity, HCl salt) was obtained asan orange solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.57 (s, 1H), 8.53 (d, J=5.3Hz, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.68 (d, J=5.3 Hz, 1H), 6.98-6.86(m, 1H), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 5.21 (d, J=14.8 Hz, 1H), 4.97 (brd, J=14.3 Hz, 1H), 4.84-4.78 (m, 1H), 4.64 (t, J=9.3 Hz, 1H), 4.34 (dd,J=9.8, 3.1 Hz, 1H), 4.13-3.91 (m, 2H). LCMS (ESI+): m/z 424.0 (M+H).

Example 119:(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-chloro-3-methyl-2-(trimethylstannyl)pyridine

A mixture of 2-bromo-5-chloro-3-methylpyridine (150 mg, 727 umol, 1.00eq), trimethyl(trimethylstannyl)stannane (476 mg, 1.45 mmol, 301 uL,2.00 eq), Pd(PPh₃)₄ (84.0 mg, 72.7 umol, 0.100 eq) in dioxane (5.00 mL)was degassed and purged with nitrogen 3 times, and the mixture wasstirred at 100° C. for 12 hr under nitrogen atmosphere. The obtainedsolution of 5-chloro-3-methyl-2-(trimethylstannyl)pyridine was used inthe next step without further purification.

Step 2: tert-butyl(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

A mixture of 5-chloro-3-methyl-2-(trimethylstannyl)pyridine (211 mg, 727umol, 2.38 eq) in dioxane (5.00 mL), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), Pd(PPh₃)₄ (35.3 mg, 30.5 umol, 0.100 eq),LiCl (19.4 mg, 458 umol, 9.37 uL, 1.50 eq) and CuI (29.1 mg, 153 umol,0.500 eq) was degassed and purged with nitrogen 3 times, and then themixture was stirred at 100° C. for 16 h under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/1).tert-butyl(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(127 mg, crude) was obtained as a yellow oil.

Step 3:(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 223 umol, 1.00 eq) in TFA (2.00 mL) and DCM (4.00 mL) wasstirred at 25° C. for 1 hr under nitrogen atmosphere. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 20%-45%, 10 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-4-(5-chloro-3-methylpyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(17.1 mg, 36.0 umol, 16% yield, 99.9% purity, HCl salt) was obtained asa light yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.54 (s, 1H), 8.58 (d,J=1.8 Hz, 1H), 8.21 (s, 1H), 7.96 (d, J=1.7 Hz, 1H), 6.94 (t, 7=9.5 Hz,1H), 6.70 (dd, 7=8.7, 3.9 Hz, 1H),5.21 (d,7=14.8 Hz, 1H), 5.00 (br d,7=14.8 Hz, 1H), 4.77 (br d, 7=5.0 Hz, 1H), 4.63 (t, 7=9.4 Hz, 1H), 4.33(dd, 7=9.7, 3.3 Hz, 1H), 4.17-4.03 (m, 1H), 4.02-3.89 (m, 1H), 2.50 (s,3H). LCMS (ESI+): m/z 438.0 (M+H).

Example 120:(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-chloro-5-fluoro-2-iodopyridine

To a solution of 3-chloro-5-fluoropyridin-2-amine (450 mg, 3.07 mmol,1.00 eq) and CuI (1.17 g, 6.14 mmol, 2.00 eq) in MeCN (8.00 mL) wasadded isopentyl nitrite (791 mg, 6.76 mmol, 910 uL, 2.20 eq) in MeCN(2.00 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred at0° C. for 1 hr and then the mixture was stirred at 60° C. for 12 h undernitrogen atmosphere. The reaction was filtered, water (10.0 mL) wasadded to the filtrate. The obtained solution was extracted with ethylacetate (10.0 mL*3), the combined organic layers were dried over MgSO₄,and concentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Petroleum ether/Ethyl acetate=10/1).3-Chloro-5-fluoro-2-iodopyridine (230 mg, 893 umol, 29% yield) wasobtained as a white solid.

Step 2: tert-butyl(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq) in dioxane (6.00 mL) were added3-chloro-5-fluoro-2-iodopyridine (147 mg, 570 umol, 2.00 eq), Pd(PPh₃)₄(33.0 mg, 28.5 umol, 0.100 eq), CuI (21.7 mg, 114 umol, 0.400 eq) andLiCl (24.2 mg, 570 umol, 11.7 uL, 2.00 eq) at 20° C. The mixture wasstirred at 100° C. for 12 h under nitrogen atmosphere. The reactionmixture was filtered, the filtrate was concentrated. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-butyl(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, crude) was obtained as a yellow oil.

Step 3:(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 148 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100° C.for 3 h. The reaction was concentrated. The residue was dissolved inDMSO (4.00 mL). The suspension was purified by acidic prep-HPLC (column:Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water (0.04%HCl)-ACN]; B %: 20%-45%, 10 min). The product-containing fraction wasconcentrated under reduced pressure to remove most of MeCN at 30° C. andthe aqueous phase was lyophilized.(S)-4-(3-chloro-5-fluoropyridin-2-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(12.5 mg, 26.1 umol, 17% yield, 99.8% purity, HCl) was obtained as agreen solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.52 (s, 1H), 8.63 (d, J=2.4 Hz,1H), 8.51 (s, 1H), 8.05 (dd, J=8.0, 2.3 Hz, 1H), 6.92 (t, J=9.6 Hz, 1H),6.68 (dd, J=8.7, 3.6 Hz, 1H), 5.20 (d, J=15.0 Hz, 1H), 4.98 (br d,J=15.0 Hz, 1H), 4.76 (brs, 1H), 4.61 (t, 7=9.5 Hz, 1H),4.31 (dd, J=9.7,3.1 Hz, 1H), 4.06 (br d, 7=9.7 Hz, 1H), 3.97-3.89 (m, 1H). LCMS (ESI+):m/z 442.0 (M+H).

Example 121:(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 1,4,5-trimethyl-1H-imidazole

To a solution of 4,5-dimethyl-1H-imidazole (500 mg, 3.77 mmol, 1.00 eq,HCl) in THF (8.00 mL) was added NaH (377 mg, 9.43 mmol, 60% purity, 2.50eq) at 20° C. under N₂. The mixture was stirred at 20° C. for 0.5 hr.Mel (500 mg, 3.52 mmol, 219 uL, 0.934 eq) was added to the mixture at20° C. The mixture was stirred at 20° C. for 1 hr. The reaction mixturewas quenched by addition of MeOH (2.00 mL) at 0° C. and the mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobilephase: [water (0.04% NH₃ water+10 mM NH₄HCO₃)-ACN]; B %: 1%-15%, 10min). 1,4,5-Trimethyl-1H-imidazole (300 mg, crude) was obtained as ayellow liquid.

Step 2: tert-butyl(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq) in dioxane (2.00 mL) and EtOH (1.00 mL) in amicrowave tube with a stir bar were added 1,4,5-trimethyl-1H-imidazole(100 mg, 908 umol, 2.23 eq), Pd(OAc)₂ (24.0 mg, 107 umol, 0.263 eq),PPh₃ (56.0 mg, 214 umol, 0.524 eq) and Na₂CO₃ (129 mg, 1.22 mmol, 3.00eq) under argon. The tube was sealed with a silicon septum and subjectedto microwave irradiation at 150° C. with stirring for 2 h The reactionmixture was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-butyl(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, crude) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 192 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.00 mL) at20° C. The mixture was stirred at 20° C. for 2 h. The reaction mixturewas concentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 20%-40%, 10 min).(S)-12-fluoro-4-(1,4,5-trimethyl-1H-imidazol-2-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(65.0 mg, 141 umol, 73% yield, 99.4% purity, HCl salt) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.58 (s, 1H), 8.08 (s, 1H),7.00-6.89 (m, 1H), 6.70 (dd, J=8.7, 4.8 Hz, 1H), 5.23 (d, J=14.8 Hz,1H), 5.00 (br d, J=14.8 Hz, 1H), 4.78 (br s, 1H), 4.65 (t, J=9.6 Hz,1H), 4.33 (dd, J=9.8, 3.2 Hz, 1H), 4.14-4.04 (m, 1H), 4.01-3.90 (m, 1H),3.71 (s, 3H), 2.39 (s, 6H). LCMS (ESI+): m/z 421.0 (M+H).

Example 122:(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 5-methylpyrimidin-4-yl trifluoromethanesulfonate

To a stirred solution of 5-methylpyrimidin-4-ol (300 mg, 2.72 mmol, 1.00eq) and DIPEA (704 mg, 5.45 mmol, 949 uL, 2.00 eq) in DCM (5.00 mL) wasadded1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(1.17 g, 3.27 mmol, 1.20 eq) at 25° C. The resulting mixture was stirredat 25° C. for 12 h. To the mixture was added water (10.0 mL) and themixture was extracted with EtOAc (10.0 mL*3). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was purified by prep-TLC (SiO₂, PE/EtOAc=10/1).5-Methylpyrimidin-4-yl trifluoromethanesulfonate (240 mg, 991 umol, 36%yield) was obtained as yellow oil.

Step 2: tert-butyl(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To 5-methylpyrimidin-4-yl trifluoromethanesulfonate (240 mg, 992 umol,3.48 eq) and tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 285 umol, 1.00 eq) in dioxane (5.00 mL) were added CuI (21.7mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 570 umol, 11.7 uL, 2.00 eq) andPd(PPh₃)₄ (33.0 mg, 28.5 umol, 0.100 eq) at 25° C. under N₂. Theresulting mixture was stirred at 80° C. for 12 h. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE/EtOAc=0/1). tert-butyl(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 238 umol, 83% yield) was obtained as a yellow solid.

Step 3:(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 238 umol, 1.00 eq) was added HFIP (4.00 mL) at 25° C. Themixture was stirred at 80° C. for 12 h. The mixture was concentratedunder reduced pressure. The mixture was purified by acidic prep-HPLC(HCl conditions).(S)-12-fluoro-4-(5-methylpyrimidin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(34.4 mg, 76.2 umol, 32% yield, 97.6% purity, HCl salt) was obtained asan orange solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.57 (s, 1H), 9.18 (s, 1H),8.84 (s, 1H), 8.45 (s, 1H), 7.03-6.89 (m, 1H), 6.72 (dd, 7=8.6, 4.0 Hz,1H), 5.27 (d, J=15.0 Hz, 1H), 5.04 (br d, J=15.6 Hz, 1H), 4.85-4.78 (m,1H), 4.65 (t, J=9.4 Hz, 1H), 4.35 (dd, J=9.7, 3.5 Hz, 1H), 4.17-4.06 (m,1H), 4.05-3.95 (m, 1H), 2.65 (s, 3H). LCMS (ESI+): m/z 405.0 (M+H).

Example 123:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-olStep 1: methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate

Methylhydrazine (6.61 g, 57.4 mmol, 7.56 mL, 40.0% in water, 1.00 eq)were added to dimethyl 3-oxopentanedioate (10.0 g, 57.4 mmol, 8.26 mL,1.00 eq) in MeOH (100 mL) at 20° C., during which the reactiontemperature rose to 65° C. After completion of the addition, the mixturewas stirred for a further 2 h and NaOMe (10.3 g, 57.4 mmol, 30.0% inMeOH, 1.00 eq) was then added at 65° C. The reaction was slightlyexothermic. The reaction mixture was stirred for a further 4 h TLC(Petroleum ether:Ethyl acetate=0:1) indicated no dimethyl3-oxopentanedioate was remained, and one major new spot with largerpolarity was detected. The reaction mixture was concentrated underreduced pressure to remove solvent, and the residue was dissolved inwater (40.0 mL). After acidification with glacial acetic acid to pH=5the mixture was extracted with EtOAc (50.0 mL*3). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was suspended in EtOAc (30.0 mL) and filtered, thefilter cake was dried and collected. Methyl2-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (4.50 g, crude) wasobtained as a white solid.

Step 2: methyl 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetate

Twenty parallel reactions were set up. To a solution of methyl2-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (100 mg, 588 umol, 1.00eq) in MeCN (4.00 mL) was added POBr₃ (842 mg, 2.94 mmol, 299 uL, 5.00eq) at 20° C. The mixture was stirred at 80° C. for 12 h. All batcheswere combined and quenched by addition of sat. aq. NaHCO₃ (50.0 mL) at0° C. Then the mixture was extracted with EtOAc (70.0 mL*3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1). Methyl2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetate (1.20 g, crude) was obtainedas a yellow liquid.

Step 3: 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-ol

To a solution of methyl 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetate (600mg, 2.57 mmol, 1.00 eq) in DCM (10.0 mL) was added DIBAL-H (1.00 M, 9.01mL, 3.50 eq) at 0° C. under N₂. The mixture was stirred at 25° C. for 12h The reaction mixture was quenched by addition of MeOH (5.00 mL) at 0°C., and the mixture was concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether/EtOH=1/0 to20/1). 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-ol (200 mg, crude)was obtained as a yellow liquid.

Step 4: 2-(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)ethan-1-ol

To a solution of 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-ol (200 mg,975 umol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 819 uL,2.10 eq) at −70° C. under N₂. The mixture was stirred at −70° C. for 0.5hr. Tributyl(chloro)stannane (476 mg, 1.46 mmol, 393 uL, 1.50 eq) wasadded to the mixture at −70° C. which was then stirred at −70° C. for 1hr. The reaction mixture was quenched by addition of sat. aq. KF (1.00mL) at 0° C. The mixture was extracted with MTBE (10.0 mL*3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure.2-(l-Methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)ethan-1-ol (350 mg,crude) was obtained as a yellow liquid.

Step 5: tert-butyl(S)-12-fluoro-4-(3-(2-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq) in dioxane (5.00 mL) were added2-(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)ethan-1-ol (338 mg, 814umol, 2.00 eq), Pd(PPh₃)₄ (47.0 mg, 40.7 umol, 0.100 eq), CuI (31.0 mg,162 umol, 0.400 eq) and LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00 eq) at20° C. under N₂. The mixture was stirred at 90° C. for 12 h. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-butyl(S)-12-fluoro-4-(3-(2-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, crude) was obtained as a brown solid.

Step 6:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-ol

A mixture of tert-butyl(S)-12-fluoro-4-(3-(2-hydroxyethyl)-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 224 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C. for2 h The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10 um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 20%-45%, 10min).(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-ol(53.0 mg, 120 umol, 53% yield, 99.1% purity) was obtained as a whitesolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.44 (s, 1H), 7.64 (br t, J=6.4 Hz,1H), 7.39 (s, 1H), 6.96 (dd, J=10.1, 8.8 Hz, 1H), 6.69 (dd, J=8.6, 4.0Hz, 1H), 6.39 (s, 1H), 4.96-4.87 (m, 1H), 4.84-4.72 (m, 1H), 4.66 (t,J=5.2 Hz, 1H), 4.59-4.45 (m, 2H), 4.21 (dd, J=9.6, 3.6 Hz, 1H),4.09-3.98 (m, 1H), 3.93-3.82 (m, 1H), 3.74 (s, 3H), 3.65 (dt, J=7.2, 5.4Hz, 2H), 2.70 (t, J=7.2 Hz, 2H). LCMS (ESI+): m/z 437.0 (M+H).

Example 124:(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-iodo-2,5-dimethylpyridine

To a solution of 2,5-dimethylpyridin-4-amine (500 mg, 4.09 mmol, 1.00eq), CuI (1.01 g, 5.32 mmol, 1.30 eq) in MeCN (10.0 mL) was addedisopentyl nitrite (719 mg, 6.14 mmol, 826 uL, 1.50 eq) in MeCN (5.00 mL)at 0° C. The mixture was stirred at 60° C. for 12 h The reaction mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 10/1).4-Iodo-2,5-dimethylpyridine (320 mg, 1.37 mmol, 33% yield) was obtainedas a yellow solid.

Step 2: tert-butyl(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of 4-iodo-2,5-dimethylpyridine (73.1 mg, 314 umol, 1.10eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Ex. 16; 200 mg, 285 umol, 1.00 eq) in dioxane (2.00 mL) were added CuI(21.7 mg, 114 umol, 0.400 eq), LiCl (24.2 mg, 571 umol, 11.7 uL, 2.00eq) and Pd(PPh₃)₄ (33.0 mg, 28.6 umol, 0.100 eq) at 20° C., then themixture stirred at 80° C. for 12 h under N₂. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=0:1). tert-butyl(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(70.0 mg, 135 umol, 47% yield) was obtained as a yellow solid.

Step 3:(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(70.0 mg, 135 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C., themixture was stirred at 100° C. for 2 h under N₂. The reaction mixturewas concentrated under reduced pressure. The residue was purified byprep-HPLC (HCl conditions).(S)-4-(2,5-dimethylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(24.7 mg, 54.3 umol, 40% yield, 99.7% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.59 (s, 1H), 8.77 (s, 1H),8.09 (s, 1H), 7.99 (s, 1H), 6.95 (br t, J=9.5 Hz, 1H), 6.71 (br dd,J=8.6, 3.9 Hz, 1H), 5.24 (br d, J=14.8 Hz, 1H), 5.04-4.94 (m, 1H), 4.85(br s, 1H), 4.65 (br t, J=9.5 Hz, 1H), 4.33 (br dd, J=9.6, 3.2 Hz, 1H),4.08 (br d, J=8.6 Hz, 1H), 3.94 (br t, J=10.8 Hz, 1H), 2.82 (s, 3H),2.43 (s, 3H). LCMS (ESI+): m/z 418.0 (M+H).

Example 125:(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-chloro-2-methylpyridin-4-amine

To a solution of 2-methylpyridin-4-amine (3.00 g, 27.7 mmol, 1.00 eq) inMeCN (20.0 mL) was added NCS (4.07 g, 30.5 mmol, 1.10 eq) in MeCN (10.0mL) at 0° C. The mixture was stirred at 0° C. for 2 h. The reactionmixture was concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 0/1). 3-chloro-2-methylpyridin-4-amine (2.01 g, 14.1mmol, 50% yield) was obtained as a gray solid.

Step 2: 3-chloro-4-iodo-2-methylpyridine

To a solution of 3-chloro-2-methylpyridin-4-amine (2.01 g, 14.1 mmol,1.00 eq), CuI (3.49 g, 18.3 mmol, 1.30 eq) in MeCN (20.0 mL) was addedisopentyl nitrite (2.48 g, 21.2 mmol, 2.85 mL, 1.50 eq) in MeCN (10.0mL) at 0° C. The mixture was stirred at 60° C. for 2 h under N₂. Thereaction mixture concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 10/1). 3-chloro-4-iodo-2-methylpyridine (350 mg, 1.38mmol, 9% yield) was obtained as a yellow solid.

Step 3: (3-chloro-2-methylpyridin-4-yl)boronic acid

To a solution of 3-chloro-4-iodo-2-methylpyridine (350 mg, 1.38 mmol,1.00 eq) in THF (5.00 mL) at −78° C. was added n-BuLi (2.50 M, 829 uL,1.50 eq). The mixture was stirred at −78° C. for 0.5 hr. And to themixture was added triisopropyl borate (779 mg, 4.14 mmol, 952 uL, 3.00eq) at −78° C. The mixture was stirred at −78° C. for 1 hr under N₂. Thereaction mixture was quenched by addition of MeOH (2.00 mL) at −78° C.,the reaction mixture was concentrated under reduced pressure.(3-Chloro-2-methylpyridin-4-yl)boronic acid (235 mg, crude) was obtainedas a yellow solid.

Step 4: tert-butyl(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of (3-chloro-2-methylpyridin-4-yl)boronic acid (235 mg,1.37 mmol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL) were addedtert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(222 mg, 452 umol, 0.330 eq), Pd(dppf)Cl₂ (10.0 mg, 13.7 umol, 0.0100eq) and NaHCO₃ (230 mg, 2.74 mmol, 2.00 eq) at 20° C. The mixture wasstirred at 80° C. for 12 h under N₂. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=1:3). tert-butyl(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(72.0 mg, 134 umol, 9% yield) was obtained as a yellow solid.

Step 5:(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(70.0 mg, 130 umol, 1.00 eq) was added HFIP (2.00 mL) at 20° C., themixture was stirred at 80° C. for 12 h under N₂. The reaction mixtureconcentrated under reduced pressure. The residue was purified byprep-HPLC (HCl conditions).(S)-4-(3-chloro-2-methylpyridin-4-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(15.9 mg, 32.9 umol, 25% yield, 98.0% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.56 (br s, 1H), 8.67 (br d,J=5.5 Hz, 1H), 8.14 (br s, 1H), 7.79 (br d, J=5.5 Hz, 1H), 6.95 (br t,J=9.5 Hz, 1H), 6.71 (br dd, J=8.7, 3.9 Hz, 1H), 5.24 (br d, J=14.8 Hz,1H), 4.99 (br d, J=14.5 Hz, 1H), 4.80 (br s, 1H), 4.65 (br t, J=9.5 Hz,1H), 4.34 (br dd, J=9.8, 3.2 Hz, 1H), 4.13-4.04 (m, 1H), 4.01-3.90 (m,1H), 2.85 (br s, 3H). LCMS (ESI+): m/z 438.1 (M+H).

Example 126:(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-bromo-5-chloro-2-methylpyridine

To a solution of 5-bromo-6-methylpyridin-3-amine (2.00 g, 10.7 mmol,1.00 eq) and CuCl (2.12 g, 21.4 mmol, 511 uL, 2.00 eq) in MeCN (20.0 mL)was added isopentyl nitrite (3.13 g, 26.7 mmol, 3.60 mL, 2.50 eq) at 0°C. The mixture was stirred at 0° C. for 1 hr. The mixture was stirred at80° C. for 12 h under N₂. LCMS showed the reaction was complete. Themixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 10/1) to give3-bromo-5-chloro-2-methylpyridine (850 mg, crude) as yellow oil.

Step 2:5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 3-bromo-5-chloro-2-methylpyridine (600 mg, 2.91 mmol,1.00 eq) and Pin₂B₂ (886 mg, 3.49 mmol, 1.20 eq) in dioxane (7.00 mL)were added Pd(dppf)Cl₂ (213 mg, 291 umol, 0.100 eq) and KOAc (570 mg,5.81 mmol, 2.00 eq) at 25° C. The mixture was stirred at 80° C. for 2 hunder N₂. The mixture was concentrated under reduced pressure to give5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(2.00 g, crude) as a black solid.

Step 3: tert-butyl(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 204 umol, 1.00 eq) and5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(310 mg, 1.22 mmol, 6.00 eq) in dioxane (4.00 mL) and water (0.800 mL)were added Na₂CO₃ (43.2 mg, 407 umol, 2.00 eq) and Pd(dppf)Cl₂ (14.9 mg,20.4 umol, 0.100 eq) at 25° C. The mixture was stirred at 80° C. for 12h under N₂. The mixture was combined with the other batches (from 100 mgof tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate).The mixture was filtered and the filtrate was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether:Ethyl acetate=1:1) to give tert-butyl(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, crude) was obtained as yellow oil.

Step 4:(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 279 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.5mmol, 1.00 mL, 48.4 eq) at 25° C. The mixture was stirred at 25° C. for1 hr. LCMS showed that the reaction was complete. The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (HCl condition).(S)-4-(5-chloro-2-methylpyridin-3-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(43.6 mg, 90.5 umol, 32% yield, 98.4% purity, HCl) was obtained as ayellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 10.03 (s, 1H), 8.85 (br s,1H), 8.65 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.94 (s, 1H),7.07-6.96 (m, 1H), 6.74 (dd, J=8.6, 3.9 Hz, 1H), 5.09-4.95 (m, 1H),4.89-4.85 (m, 1H), 4.57 (br t, J=9.4 Hz, 2H), 4.24 (dd, J=9.7, 3.6 Hz,1H), 4.07-4.03 (m, 1H), 3.97-3.86 (m, 1H), 2.38 (s, 3H). LCMS (ESI+):m/z 438.1 (M+H).

Example 127:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylethan-1-amineStep 1: (5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methane sulfonate

To a solution of (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol (1.80 g,9.42 mmol, 1.00 eq) in DCM (20.0 mL) was added TEA (1.43 g, 14.1 mmol,1.97 mL, 1.50 eq) and MsCl (2.16 g, 18.9 mmol, 1.46 mL, 2.00 eq) at 0°C. Then the mixture was stirred at 0° C. for 30 mins. Saturated NaHCO₃solution was added to the mixture to adjust pH to neutral. Then themixture was extracted with EtOAc (10.0 mL*4). The combined organiclayers were washed with brine (5.00 mL), dried over anhydrous Na₂SO₄,filtered, and the filtrate was concentrated under reduced pressure.5-Bromo-1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate (2.20 g, crude)was obtained as yellow oil.

Step 2: 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile

The reaction was set up in 10 parallel batches. To5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate (220 mg, 817umol, 1.00 eq) in MeCN (2.00 mL) was added TMSCN (122 mg, 1.23 mmol, 154uL, 1.51 eq) and TBAF (1.00 M, 1.23 mL, 1.50 eq) at 20° C. The mixturewas stirred at 20° C. for 12 h. The 10 batches were combined. Thereaction mixture was concentrated under reduced pressure followed byaddition of water (20.0 mL). The mixture was extracted with EtOAc (20.0mL*5). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, PE:EtOAc=1:1).2-(5-Bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile (740 mg, crude) wasobtained as yellow oil.

Step 3: 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-amine

To 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile (800 mg, 4.00 mmol,1.00 eq) in THF (10.0 mL) was added BH₃.THF (1.00 M, 24.0 mL, 6.00 eq)dropwise at 0° C. The mixture was stirred at 60° C. for 12 h undernitrogen atmosphere. MeOH (10.0 mL) was added to the mixture. Themixture was concentrated under reduced.2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-amine (800 mg, crude) wasobtained as colourless oil.

Step 4: tert-butyl (2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethyl)carbamate

To 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethan-1-amine (800 mg, 3.92 mmol,1.00 eq) and Boc₂O (1.71 g, 7.84 mmol, 1.80 mL, 2.00 eq) in DCM (5.00mL) was added TEA (792 mg, 7.83 mmol, 1.09 mL, 2.00 eq) at 20° C. Themixture was stirred at 20° C. for 3 hr. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE:EtOAc=1:1). tert-Butyl(2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethyl)carbamate (430 mg, crude) wasobtained as yellow oil.

Step 5: tert-butyl(S)-4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To tert-butyl (2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethyl)carbamate (182mg, 599 umol, 1.50 eq) and tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(280 mg, 399 umol, 1.00 eq) in dioxane (4.00 mL) was added palladiumtritert-butylphosphane (20.4 mg, 39.9 umol, 0.100 eq) at 20° C. Themixture was stirred at 80° C. for 2 hr under nitrogen atmosphere. LC-MSindicated partial conversion. The mixture stirred at 80° C. foradditional 2 h. LC-MS showed incompleted reaction. tert-Butyl(2-(5-bromo-1-methyl-1H-pyrazol-3-yl)ethyl)carbamate (50.0 mg, 164 umol,4.12e-1 eq) and palladium tritert-butylphosphane (20.4 mg, 39.9 umol,0.100 eq) were added to the mixture. The mixture was stirred at 100° C.for 1 hr. LC-MS showed complete conversion. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, EtOAc). tert-Butyl(S)-4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, crude) was obtained as yellow oil.

Step 6:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-amine

To tert-butyl(S)-4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 189 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (462 mg, 4.05mmol, 0.300 mL, 21.5 eq) at 20° C. The mixture was stirred at 20° C. for1 hr. DIPEA was added to the mixture to adjust pH to 7-8. The reactionmixture was concentrated under reduced pressure. The product (90.0 mg,crude) was obtained as yellow oil.

Step 7:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylethan-1-amine

The reaction was set up in 7 parallel batches. To(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)ethan-1-amine(20.0 mg, 45.9 umol, 1.00 eq) and formaldehyde (18.6 mg, 230 umol, 17.1uL, 5.00 eq) in MeOH (2.00 mL) was added AcOH (2.76 mg, 45.9 umol, 2.63uL, 1.00 eq) at 20° C. NaBH₃CN (5.77 mg, 91.9 umol, 2.00 eq) was addedto each mixture and it was stirred at 20° C. for 2 h. The batches werecombined. The mixture was concentrated. The crude product was purifiedby prep-HPLC (basic conditions) to afford the product as a free base. Tothe product was added aqueous HCl (0.05 mL, 37%) and the obtained saltwas lyophilized.(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylethan-1-amine(13.6 mg, HCl salt) was obtained as yellow solid. ¹H NMR CD₃OD 400 MHzδ=ppm 9.58 (s, 1H), 8.04 (s, 1H), 6.91 (dd, J=10.0, 8.9 Hz, 1H), 6.68(dd, J=8.7, 3.9 Hz, 1H), 6.52 (s, 1H), 5.19 (d, J=14.8 Hz, 1H),5.01-5.00 (m, 1H), 4.99 (br s, 1H), 4.76 (br d, J=6.2 Hz, 1H), 4.62 (t,J=9.5 Hz, 1H), 4.31 (dd, J=9.7, 3.1 Hz, 1H), 4.15-4.01 (m, 1H),3.97-3.87 (m, 1H), 3.77 (s, 3H), 3.53 (t, J=7.3 Hz, 2H), 3.16 (t, J=7.2Hz, 2H), 2.97 (s, 6H). LCMS (ESI+): m/z 464.3 (M+H).

Example 128:(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 14-(tert-butyl) 4-methyl(S)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4,14(8H)-dicarboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(4.50 g, 9.16 mmol, 1.00 eq) in MeOH (200 mL) was added TEA (9.27 g,91.6 mmol, 12.8 mL, 10.0 eq) and Pd(dppf)Cl₂ (670 mg, 916 umol, 0.100eq) at 20° C., stirred at 60° C. for 12 h under CO (50 psi). TLC(Petroleum ether/Ethyl acetate=0/1) showed the reaction was complete.The mixture was concentrated and water (50.0 mL) and EtOAc (50.0 mL)were added to the solution. Brown precipitate was filtered off and driedto give 14-(tert-butyl) 4-methyl(S)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4,14(8H)-dicarboxylate(3.8 g, crude) as a brown solid.

Step 2:(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid

To a solution of 14-(tert-butyl) 4-methyl(S)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4,14(8H)-dicarboxylate(4.10 g, 8.72 mmol, 1.00 eq) in MeOH (60.0 mL), water (20.0 mL) and THF(60.0 mL) was added NaOH (697 mg, 17.4 mmol, 2.00 eq) at 20° C. andstirred at 20° C. for 1 hr. The mixture was concentrated, water (50.0mL) was added to the solution. The mixture was extracted with EtOAc (100mL*3), the aqueous phase was adjusted to pH of 2 with HCl (1 M), andextracted with EtOAc (50.0 mL*3). All organic layers were combined,dried over Na₂SO₄, then concentrated.(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid (3.20 g, 7.01 mmol, 80% yield) was obtained as a yellow solid.

Step 3: tert-butyl(S)-4-carbamoyl-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid (2.00 g, 4.39 mmol, 1.00 eq) in DMF (20.0 mL) were added DIPEA(2.27 g, 17.6 mmol, 3.06 mL, 4.00 eq), HOBt (1.19 g, 8.78 mmol, 2.00 eq)and EDCI (1.68 g, 8.78 mmol, 2.00 eq) at 20° C. The mixture was stirredat 20° C. for 5 min. NH₄Cl (470 mg, 8.79 mmol, 2.00 eq) was added to themixture at 20° C. The mixture was stirred at 20° C. for 12 h. LC-MSshowed(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid was consumed completely and one main peak with desired mass wasdetected. The mixture was combined with the pilot batch (same reaction,from 200 mg of(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid) for the workup. Water (10.0 mL) was added to the mixture and itwas extracted with ethyl acetate (20.0 mL*5). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 1/1).tert-butyl(S)-4-carbamoyl-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.86 g, crude) was obtained as yellow oil.

Step 4: tert-butyl(S,Z)-4-((1-(dimethylamino)ethylidene)carbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To tert-butyl(S)-4-carbamoyl-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.86 g, 4.08 mmol, 1.00 eq) was added1,1-dimethoxy-N,N-dimethyl-ethanamine (21.2 g, 159 mmol, 23.3 mL, 39.0eq) at 20° C. Then the mixture was stirred at 90° C. for 2 h Thereaction mixture was concentrated under reduced pressure. tert-Butyl(S,Z)-4-((l-(dimethylamino)ethylidene)carbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(2.00 g, crude) was obtained as brown oil.

Step 5: tert-butyl(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To tert-butyl(S,Z)-4-((l-(dimethylamino)ethylidene)carbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(2.00 g, 3.81 mmol, 1.00 eq) in AcOH (21.0 g, 350 mmol, 20.0 mL, 91.7eq) was added methylhydrazine (1.32 g, 11.4 mmol, 1.51 mL, 3.00 eq) at20° C. The mixture was stirred at 60° C. for 2 h. LC-MS showedtert-butyl(S,Z)-4-((l-(dimethylamino)ethylidene)carbamoyl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. Water (10.0 mL) was added to the mixture which was thenextracted with ethyl acetate (50.0 mL*4). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1). tert-butyl(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.20 g, crude) was obtained as yellow oil.

Step 6:(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.20 g, 2.36 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (5.10 g,44.7 mmol, 3.31 mL, 18.9 eq) at 20° C. Then the mixture was stirred at20° C. for 1 hr. The reaction mixture was concentrated under reducedpressure. The crude product was purified by prep-HPLC (formic acidconditions).(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(280 mg, 687 umol, 29% yield, N/A purity) was obtained as white solid.¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.48 (s, 1H), 7.87 (br t, J=6.3 Hz, 1H),7.59 (s, 1H), 6.96 (dd, J=10.1, 9.0 Hz, 1H), 6.70 (dd, J=8.7, 3.8 Hz,1H), 4.99-4.88 (m, 1H), 4.88-4.76 (m, 1H), 4.59-4.45 (m, 2H), 4.21 (dd,J=9.5, 3.7 Hz, 1H), 4.10-3.98 (m, 1H), 3.85 (br d, J=10.4 Hz, 1H), 3.78(s, 3H), 2.27 (s, 3H).

Step 7:(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninemesylate

To free base(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(257 mg, 631 umol, 1.00 eq) in MeCN (1.84 mL) was added MsOH (61.2 mg,637 umol, 45.4 uL, 1.01 eq) in MeCN (0.276 mL) dropwise at 50° C. Thenthe mixture was stirred at 50° C. for 1 hr, then the mixture was cooledto 30° C. in the span of 1 hr, and the mixture was stirred at 30° C. for2 h. The mixture was cooled to 25° C. and concentrated under reducedpressure to remove most of MeCN at 30° C. Water (10.0 mL) was added tothe mixture followed by lyophilization.(S)-4-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(312 mg, 599 umol, 95% yield, 96.7% purity, CH₃SO₃H salt) was obtainedas a yellow crystalline solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.62 (s,1H), 8.57-8.30 (m, 1H), 7.97 (br s, 1H), 7.00 (t, J=9.5 Hz, 1H), 6.73(dd, J=8.6, 3.7 Hz, 1H), 5.09-4.78 (m, 2H), 4.56 (br t, J=9.5 Hz, 2H),4.23 (br dd, J=9.5, 3.7 Hz, 1H), 4.14-4.02 (m, 1H), 3.95 (br s, 1H),3.88 (s, 3H), 2.34 (s, 3H), 2.32 (s, 3H). LCMS (ESI+): m/z 408.2 (M+H).

Example 129:(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-((1-iminopropyl)carbamoyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid (300 mg, 657 umol, 1.00 eq) in DMF (5.00 mL) was added DIPEA (340mg, 2.63 mmol, 458 uL, 4.00 eq), the mixture was stirred at 20° C. for 5mins. Then EDCI (252 mg, 1.31 mmol, 2.00 eq) and HOBt (178 mg, 1.31mmol, 2.00 eq) were added to the mixture at 20° C. The mixture wasstirred at 20° C. for 5 min followed by addition of propanamidine (143mg, 1.31 mmol, 2.00 eq, HCl salt) at 20° C. The mixture was stirred at20° C. for 12 hr. LC-MS showed that(S)-14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-4-carboxylicacid was consumed completely and one main peak with the desired mass wasdetected. The obtained material was used directly in the next step.

Step 2: tert-butyl(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To tert-butyl(S)-12-fluoro-4-((l-iminopropyl)carbamoyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(656 umol theoretical yield, 1.00 eq) in DMF (5.00 mL) was added AcOH(315 mg, 5.25 mmol, 300 uL, 7.99 eq) and methylhydrazine (113 mg, 981umol, 129 uL, 1.50 eq) at 20° C. The mixture was stirred at 60° C. for 2hr. LC-MS showed tert-butyl(S)-12-fluoro-4-((l-iminopropyl)carbamoyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with the desired mass wasdetected. Water (5.00 mL) was added to the mixture. The reaction mixturewas extracted with ethyl acetate (5.00 mL*5). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by prep-TLC (SiO₂,ethyl acetate). tert-Butyl(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, crude) was obtained as yellow oil.

Step 3:(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 230 umol, 1.00 eq) in DCM (1.00 mL) was added TFA (462 mg, 4.05mmol, 0.300 mL, 17.6 eq) at 20° C. The mixture was stirred at 20° C. for1 hr. The reaction mixture was concentrated under reduced pressure. Thecrude product was purified by prep-HPLC (HCl conditions).(S)-4-(3-ethyl-1-methyl-1H-1,2,4-triazol-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(13.7 mg, 29.2 umol, 12% yield, 97.6% purity, HCl salt) was obtained asyellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.54 (s, 1H), 8.18 (s, 1H),6.92 (dd, J=10.1, 8.8 Hz, 1H), 6.68 (dd, J=8.7, 3.9 Hz, 1H), 5.21 (d,J=14.8 Hz, 1H), 5.01-4.95 (m, 1H), 4.80-4.74 (m, 1H), 4.68-4.58 (m, 1H),4.31 (dd, J=9.7, 3.4 Hz, 1H), 4.11-4.04 (m, 1H), 4.01 (s, 3H), 3.99-3.91(m, 1H), 2.84 (q, 7=7.6 Hz, 2H), 1.36 (br t, J=7.5 Hz, 3H). LCMS (ESI+):m/z 422.2 (M+H).

Example 130:(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[1′,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

Two parallel reactions were set up. To a solution of tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(Example 16; 500 mg, 1.03 mmol, 1.00 eq) in dioxane (8.00 mL) and water(0.800 mL) was added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (395mg, 1.55 mmol, 1.50 eq, HCl), Pd(dppf)Cl₂ (75.3 mg, 103 umol, 0.100 eq)and NaHCO₃ (432 mg, 5.14 mmol, 5.00 eq) at 20° C. The mixture wasstirred at 80° C. for 12 h under nitrogen atmosphere. The batches werecombined, the mixture was filtered, the filtrate was concentrated. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 0/1). tert-butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(720 mg, 1.45 mmol, 70% yield) was obtained as a yellow solid.

Step 2: tert-butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a mixture of tert-butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(450 mg, 904 umol, 1.00 eq), NaN₃ (823 mg, 12.7 mmol, 14.0 eq) andsodium ascorbate (215 mg, 1.09 mmol, 1.20 eq) in dioxane (15.0 mL) andwater (3.00 mL) were added CuI (241 mg, 1.27 mmol, 1.40 eq) and(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (257 mg, 1.81 mmol, 2.00eq) at 20° C. The mixture was stirred at 110° C. for 16 h under nitrogenatmosphere. Water (15.0 mL) was added to the reaction solution, themixture was extracted with ethyl acetate (15.0 mL*3), the combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=0/1). tert-Butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(400 mg, 836 umol, 92% yield) was obtained as a yellow oil.

Step 3: tert-butyl(R,Z)-5-fluoro-9-(((hydroxyamino)methylene)amino)-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a solution of tert-butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(400 mg, 836 umol, 1.00 eq) in i-PrOH (6.00 mL) was added DMF-DMA (249mg, 2.09 mmol, 278 uL, 2.50 eq) at 20° C., the mixture was stirred at90° C. for 5 h under nitrogen atmosphere. Then NH₂OH.HCl (145 mg, 2.09mmol, 2.50 eq) was added to the mixture at 20° C., and the mixture wasstirred at 50° C. for 12 h. The reaction mixture was concentrated andthe residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=0/1). tert-Butyl(R,Z)-5-fluoro-9-(((hydroxyamino)methylene)amino)-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(390 mg, 748 umol, 89% yield) was obtained as a yellow oil.

Step 4: tert-butyl(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[1′,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(R,Z)-5-fluoro-9-(((hydroxyamino)methylene)amino)-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(460 mg, 882 umol, 1.00 eq) in THF (10.0 mL) was added TFAA (926 mg,4.41 mmol, 613 uL, 5.00 eq) at 0° C., the mixture was stirred at 50° C.for 16 hr under nitrogen atmosphere. Water (10.0 mL) was added to thereaction solution, the mixture was extracted with ethyl acetate (10.0mL*3), the combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure. tert-Butyl(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[1,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.00 g, crude) was obtained as a yellow oil.

Step 5:(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[1′,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Two parallel reactions were set up. A mixture of tert-butyl(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[1,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(500 mg, 993 umol, 1.00 eq) in HFIP (10.0 mL) was stirred at 100° C. for12 h. The batches were combined and concentrated under reduced pressure.The residue was dissolved in MeOH (5.00 mL). The mixture was purified byacidic prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobilephase: [water (0.05% HCl)-ACN]; B %: 10%-40%, 10 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-12-fluoro-4-(2-methylpyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[1,5′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 227 umol, 11% yield, 100% purity, HCl salt) was obtained as awhite solid. ¹H NMR CD₃OD 400 MHz δ=ppm 8.81 (dd, J=6.0, 1.5 Hz, 1H),8.79 (s, 1H), 8.57 (dd, 7=8.2, 1.3 Hz, 1H), 8.02 (dd, 7=7.8, 6.1 Hz,1H), 7.91 (s, 1H), 6.94-6.84 (m, 1H), 6.66 (dd, J=8.7, 3.9 Hz, 1H), 5.16(d, J=14.8 Hz, 1H), 4.97 (br d, 7=14.8 Hz, 1H), 4.82-4.76 (m, 1H), 4.61(t, 7=9.4 Hz, 1H), 4.31 (dd,7=9.8, 3.0 Hz, 1H), 4.10-3.88 (m, 2H), 2.66(s, 3H). LCMS (ESI+): m/z 404.1 (M+H).

Example 131:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrileStep 1: (5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methane sulfonate

To (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol (1.60 g, 8.38 mmol, 1.00eq) in DCM (15.0 mL) was added TEA (1.70 g, 16.8 mmol, 2.33 mL, 2.00 eq)and MsCl (1.92 g, 16.8 mmol, 1.30 mL, 2.00 eq) at 0° C. The mixture wasstirred at 0° C. for 1 hr. Saturated NaHCO₃ was added to the mixture toadjust pH to 7.0. The mixture was extracted with EtOAc (10.0 mL*4). Thecombined organic layers were washed with brine (5.00 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated under reduced pressure togive (5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate (2.00 g,crude) as a yellow oil.

Step 2: 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile

The reaction was set up in 20 parallel batches. To(5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate (100 mg, 372umol, 1.00 eq) in MeCN (1.00 mL) was added TMSCN (55.3 mg, 557 umol,69.7 uL, 1.50 eq) and TBAF (LOOM, 557 uL, 1.50 eq) at 25° C. The mixturewas stirred at 25° C. for 12 h. LC-MS showed(5-bromo-1-methyl-1H-pyrazol-3-yl)methyl methanesulfonate was consumedcompletely and one main peak with desired mass was detected. The batcheswere combined and concentrated under reduced pressure. Water (30.0 mL)was added to the mixture. The mixture was extracted with EtOAc (50.0mL*4). The combined organic layers were concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 1/1).2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile (800 mg, crude) wasobtained as a yellow solid.

Step 3: 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

To NaH (390 mg, 9.75 mmol, 60% purity, 3.00 eq) was added THF (4.00 mL)at 25° C. The mixture was degassed and purged with nitrogen 3 times, themixture was stirred at 0° C. for 10 mins. Then2-(5-bromo-1-methyl-1H-pyrazol-3-yl)acetonitrile (650 mg, 3.25 mmol,1.00 eq) in THF (1.00 mL) was added to the mixture at 0° C. The mixturewas stirred at 0° C. for 0.5 hr under nitrogen atmosphere. Mel (1.84 g,13.0 mmol, 809 uL, 4.00 eq) was added at 0° C. The mixture was stirredat 0° C. for 1 hr under nitrogen atmosphere. Water (5.00 mL) was addedto the mixture. The mixture was extracted with EtOAc (20.0 mL*3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, PE:EtOAc=2:1).2-(5-bromo-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (550 mg,crude) was obtained as a yellow oil.

Step 4:2-methyl-2-(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)propanenitrile

To 2-(5-bromo-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (220 mg,965 umol, 1.00 eq) in THF (3.00 mL) was added i-PrMgCl—LiCl (1.30 M,1.48 mL, 2.00 eq) at −78° C. under N₂. Then the mixture was stirred at0° C. for 0.5 hr under N₂. Then tributyl(chloro)stannane (628 mg, 1.93mmol, 519 uL, 2.00 eq) was added into the mixture at 0° C. under N₂. Themixture was stirred at 0° C. for 1 hr under N₂. Water (5.00 mL) wasadded to the mixture. Then the mixture was extracted with ethyl acetate(10.0 mL*3), the combined organic layers were dried over anhydrousNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure.2-methyl-2-(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)propanenitrile(450 mg, crude) was obtained as a yellow oil.

Step 5: tert-butyl(S)-4-(3-(2-cyanopropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To2-methyl-2-(1-methyl-5-(tributylstannyl)-1H-pyrazol-3-yl)propanenitrile(268 mg, 611 umol, 1.50 eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 407 umol, 1.00 eq) in dioxane (3.00 mL) was added Pd(PPh₃)₄(47.0 mg, 40.7 umol, 0.100 eq), LiCl (34.5 mg, 814 umol, 16.7 uL, 2.00eq) and CuI (31.0 mg, 163 umol, 0.400 eq) at 25° C. The mixture wasstirred at 80° C. for 12 hr under N₂. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-Butyl(S)-4-(3-(2-cyanopropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, crude) was obtained as a yellow oil.

Step 6:(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4″,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile

To tert-butyl(S)-4-(3-(2-cyanopropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, 322 umol, 1.00 eq) was added HFIP (2.00 mL) at 25° C., themixture was stirred at 100° C. for 12 h. The mixture was combined withanother batch from 20 mg of tert-butyl(S)-4-(3-(2-cyanopropan-2-yl)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate.The mixture was concentrated under reduced pressure. The crude productwas purified by prep-HPLC (formic acid conditions).(S)-2-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-yl)-2-methylpropanenitrile(74.3 mg, 143 umol, 97.5% purity, formate salt) was obtained as alight-yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.45 (s, 1H), 7.70 (brt, J=6.2 Hz, 1H), 7.47 (s, 1H), 6.96 (t, J=9.5 Hz, 1H), 6.70 (dd, J=8.6,3.7 Hz, 1H), 6.64 (s, 1H), 4.97-4.87 (m, 1H), 4.85-4.74 (m, 1H),4.60-4.45 (m, 2H), 4.20 (dd, J=9.6, 3.4 Hz, 1H), 4.10-3.96 (m, 1H),3.94-3.84 (m, 1H), 3.81 (s, 3H), 1.68 (s, 6H). LCMS (ESI+): m/z 460.1(M+H).

Example 132:(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 3-fluoro-1-methyl-1H-pyrazole

To NaH (488 mg, 12.2 mmol, 60% purity, 3.00 eq) in THF (1.00 mL) wasadded 3-fluoro-1H-pyrazole (350 mg, 4.07 mmol, 1.00 eq) at 0° C. undernitrogen atmosphere. The mixture was stirred at 0° C. for 0.5 hr underN₂. Mel (2.31 g, 16.3 mmol, 1.01 mL, 4.00 eq) in THF (2.00 mL) was addedto the mixture at 0° C., and the mixture was stirred at 0° C. for 1 hrunder nitrogen atmosphere. Water (5.00 mL) was added to the mixture, themixture was extracted with EtOAc (5.00 mL*3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. 3-Fluoro-1-methyl-1H-pyrazole (300mg, crude) was obtained as yellow oil. ¹H NMR CDCl₃ 400 MHz δ=ppm 7.15(t, J=2.2 Hz, 1H), 5.74 (dd, J=6.0, 2.4 Hz, 1H), 3.77 (s, 3H).

Step 2: 3-fluoro-1-methyl-5-(tributylstannyl)-1H-pyrazole

To 3-fluoro-1-methyl-1H-pyrazole (450 mg, 4.50 mmol, 1.00 eq) in THF(1.00 mL) was added n-BuLi (2.50 M, 3.60 mL, 2.00 eq) at −78° C. underN₂. The mixture was stirred at −78° C. for 30 min.Tributyl(chloro)stannane (2.93 g, 8.99 mmol, 2.42 mL, 2.00 eq) was addedto the mixture at −78° C. under N₂. The mixture was stirred at −78° C.for 1 hr under N₂. The mixture was extracted with ethyl acetate (5.00mL*3), the combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether:ethyl acetate=10:1).3-Fluoro-1-methyl-5-(tributylstannyl)-1H-pyrazole (350 mg, 899 umol, 20%yield) was obtained as a colorless oil.

Step 3: tert-butyl(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To 3-fluoro-1-methyl-5-(tributylstannyl)-1H-pyrazole (178 mg, 458 umol,1.50 eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq) in dioxane (1.00 mL) was added Pd(PPh₃)₄(35.3 mg, 30.5 umol, 0.100 eq), LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00eq) and CuI (23.3 mg, 122 umol, 0.400 eq) at 25° C. The mixture wasstirred at 100° C. for 12 h under N₂. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=1/2).tert-butyl(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, crude) was obtained as a yellow oil.

Step 4:(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 235 umol, 1.00 eq) was added HFIP (2.00 mL) at 25° C. Themixture was stirred at 100° C. for 3 h The mixture was concentratedunder reduced pressure. The crude product was purified by prep-HPLC (HClconditions).(S)-12-fluoro-4-(3-fluoro-1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(39.6 mg, 88.62 umol, 37% yield, 100% purity, HCl salt) was obtained asa light-yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.44 (s, 1H), 7.85 (s,1H), 6.90 (dd, J=10.0, 8.9 Hz, 1H), 6.67 (dd, J=8.6, 3.7 Hz, 1H), 6.12(d, J=5.7 Hz, 1H), 5.16 (d, J=14.8 Hz, 1H), 4.94 (s, 1H), 4.76-4.67 (m,1H), 4.60 (t, J=9.4 Hz, 1H), 4.30 (dd, J=9.6, 3.2 Hz, 1H), 4.09-3.98 (m,1H), 3.93-3.84 (m, 1H), 3.66 (s, 3H). LCMS (ESI+): m/z 411.0 (M+H).

Example 133:(S)-12-fluoro-4-(1,2,4-trimethyl-1H-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(7aS)-12-fluoro-4-(l-hydroxypropyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in two parallel batches. To a stirred solutionof tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(500 mg, 1.02 mmol, 1.00 eq) in THF (7.00 mL) was added i-PrMgCl—LiCl(1.30 M, 1.57 mL, 2.00 eq) at −78° C. under nitrogen, and the mixturewas stirred at 0° C. for 0.5 hr. To the mixture was added propanal (236mg, 4.07 mmol, 296 uL, 4.00 eq) at −78° C. under N₂. The resultingmixture was stirred at 25° C. for 12 h. The batches were combined. Tothe resulting mixture was added water (20.0 mL) and it was extractedwith EtOAc (10.0 mL*3). The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure. The mixture was purifiedby MPLC (SiO₂, PE/EtOAc=10/1 to 1/2). tert-Butyl(7aS)-12-fluoro-4-(l-hydroxypropyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.20 g, crude) was obtained as a brown solid.

Step 2: tert-butyl(S)-12-fluoro-4-propionyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of tert-butyl(7aS)-12-fluoro-4-(1-hydroxypropyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(1.20 g, 2.55 mmol, 1.00 eq) in DCM (30.0 mL) was added DMP (2.16 g,5.10 mmol, 1.58 mL, 2.00 eq) at 25° C. The mixture was stirred at 25° C.for 12 h. The reaction mixture was diluted with water (30.0 mL) andextracted with EtOAc (30.0 mL*3). The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE/EtOAc=1/2). tert-butyl(S)-12-fluoro-4-propionyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(240 mg, crude) was obtained as a yellow solid.

Step 3: tert-butyl (S,Z)12-fluoro-4-(2-(hydroxyimino)propanoyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateand(S,Z)-1-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-(hydroxyimino)propan-1-one

To a solution of tert-butyl(S)-12-fluoro-4-propionyl-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(240 mg, 512 umol, 1.00 eq) in DCM (3.00 mL) was added TMSCl (55.7 mg,512 umol, 65.0 uL, 1.00 eq) at −20° C. To the cooled solution was addeddropwise isoamyl nitrite (60.0 mg, 512 umol, 68.9 uL, 1.00 eq). Themixture was stirred at 25° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, EtOAc/MeOH=20/1). tert-butyl(S,Z)-12-fluoro-4-(2-(hydroxyimino)propanoyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(30.0 mg, crude) was obtained as a yellow solid.(S,Z)-1-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-(hydroxyimino)propan-1-one(50.0 mg, crude) was obtained as a white solid.

Step 4:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1,2,4-trimethyl-1H-imidazole3-oxide

To a stirred solution of(S,Z)-1-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-(hydroxyimino)propan-1-one(50.0 mg, 126 umol, 1.00 eq) in AcOH (2.00 mL) was added MeCHO (5.54 mg,126 umol, 7.06 uL, 1.00 eq) and MeNH₂ (9.77 mg, 126 umol, 30.2 uL, 40%aqueous solution, 1.00 eq) at 25° C. The resulting mixture was stirredat 100° C. for 12 h The mixture was concentrated under reduced pressure.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1,2,4-trimethyl-1H-imidazole3-oxide (55.0 mg, crude) was obtained as yellow liquid, which was usedto the next step directly.

Step 5:(S)-12-fluoro-4-(1,2,4-trimethyl-1H-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a stirred solution of(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1,2,4-trimethyl-1H-imidazole3-oxide (55.0 mg, 126 umol, 1.00 eq) in MeOH (10.0 mL) was addedRaney-Ni (30.0 mg) at 25° C. under N₂. The resulting mixture was stirredat 50° C. for 12 h under H₂ (15 psi). The mixture was concentrated underreduced pressure. The mixture was purified by acidic prep-HPLC (HClconditions) to give the crude product. The crude product was purified byacidic prep-HPLC (HCl) again.(S)-12-fluoro-4-(1,2,4-trimethyl-1H-imidazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(2.00 mg, 4.26 umol, 3% yield, 97.4% purity, HCl salt) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.53 (s, 1H), 7.98 (s, 1H),6.93 (t, J=9.4 Hz, 1H), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 5.22 (br d, J=14.7Hz, 1H), 4.96 (br d, J=14.9 Hz, 1H), 4.84-4.69 (m, 1H), 4.68-4.59 (m,1H), 4.31 (dd, J=9.6, 3.1 Hz, 1H), 4.14-4.00 (m, 1H), 3.95-3.84 (m, 1H),3.35 (s, 3H), 2.69 (s, 3H), 2.20 (br s, 3H).

¹H NMR DMSO-d₆ 400 MHz δ=ppm 14.47 (br s, 1H), 9.63 (s, 1H), 8.21 (br d,7=6.2 Hz, 1H), 7.59 (s, 1H), 7.04-6.94 (m, 1H), 6.71 (dd, 7=8.7, 3.9 Hz,1H), 5.01-4.92 (m, 1H), 4.88-4.78 (m, 1H), 4.59-4.51 (m, 1H), 4.49-4.42(m, 1H), 4.20 (dd, 7=9.6, 3.6 Hz, 1H), 4.12-4.01 (m, 1H), 3.86 (br t,7=11.1 Hz, 1H), 3.50 (br s, 3H), 2.63 (s, 3H), 2.16 (s, 3H). LCMS(ESI+): m/z 421.2 (M+H).

Example 134:(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide

To a solution of(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid (55.0 mg, 126 umol, 1.00 eq) in DMF (3.00 mL) was added NH₄Cl (20.3mg, 379 umol, 3.00 eq), DIPEA (147 mg, 1.14 mmol, 198 uL, 9.00 eq) andHATU (72.1 mg, 190 umol, 1.50 eq) at 20° C. The mixture was stirred at20° C. for 12 hr. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 40%-60%, 10 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide(8.70 mg, 18.4 umol, 14% yield, 99.3% purity, HCl salt) was obtained asa yellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 8.58 (s, 1H), 7.79 (s, 1H),7.63 (d, J=2.1 Hz, 1H), 6.80 (dd, 7=10.1, 8.9 Hz, 1H), 6.57 (dd, 7=8.7,3.9 Hz, 1H), 6.49 (d, J=2.1 Hz, 1H), 5.08 (d, J=14.7 Hz, 1H), 4.86 (brd, 7=14.8 Hz, 1H), 4.66-4.58 (m, 1H), 4.50 (t, 7=9.4 Hz, 1H), 4.19 (dd,7=9.7, 3.2 Hz, 1H), 4.02-3.90 (m, 1H), 3.88-3.76 (m, 1H), 3.69 (s, 3H).LCMS (ESI+): m/z 435.1 (M+H).

Example 135:(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid Step 1: tert-butyl(R)-9-chloro-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a solution of tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(2.00 g, 4.12 mmol, 1.00 eq) in dioxane (20.0 mL) and water (2.00 mL)was added (2-methylpyrazol-3-yl)boronic acid (780 mg 6.19 mmol, 1.50eq), Cs₂CO₃ (4.02 g, 12.4 mmol, 3.00 eq) and Pd(dppf)Cl₂ (302 mg 413umol, 0.100 eq) at 20° C. under nitrogen atmosphere. The mixture wasstirred at 90° C. for 12 h under nitrogen atmosphere. LC-MS showedtert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylatewas remained and one peak with the desired mass was detected.Pd(dppf)Cl₂ (302 mg, 413 umol, 0.100 eq) and Cs₂CO₃ (2.68 g, 8.24 mmol,2.00 eq) was added to the mixture at 20° C. under nitrogen atmosphere.The mixture was stirred at 90° C. for 18 h under nitrogen atmosphere.LC-MS showed tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylatewas consumed completely and one main peak with the desired mass wasdetected. Water (15.0 mL) and ethyl acetate (15.0 mL) was added to themixture and filtered, and the filtrate was extracted with ethyl acetate(10.0 mL*3). The organic layers were combined, washed by brine (20.0mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 1/1). tert-Butyl(R)-9-chloro-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(1.00 g, 2.05 mmol, 49% yield) was obtained as a yellow oil.

Step 2: tert-butyl(R)-9-amino-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a solution of tert-butyl(R)-9-chloro-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(950 mg, 1.95 mmol, 1.00 eq), NaN₃ (2.66 g, 41.0 mmol, 21.0 eq), sodiumascorbate (696 mg, 3.51 mmol, 1.80 eq) in dioxane (12.0 mL) and water(4.00 mL) was added CuI (780 mg, 4.09 mmol, 2.10 eq) and(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (832 mg, 5.85 mmol, 3.00eq) at 20° C. under nitrogen atmosphere. The mixture was stirred at 110°C. for 12 h under nitrogen atmosphere. LC-MS indicated incompleteconversion. NaN₃ (1.01 g, 15.6 mmol, 8.00 eq), sodium ascorbate (387 mg,1.95 mmol, 1.00 eq), CuI (372 mg, 1.95 mmol, 1.00 eq) and(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (278 mg, 1.95 mmol, 1.00eq) in dioxane (18.0 mL) and water (6.00 mL) were added to the mixtureat 20° C. under nitrogen atmosphere. The mixture was stirred at 110° C.for 18 h under nitrogen atmosphere. Saturated aqueous NaHCO₃ (20.0 mL)solution was added to mixture to adjust pH to 10, the mixture wasextracted with ethyl acetate (20.0 mL*3), the combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. NaClO (20.0 mL, 14%) was added dropwise to the aqueous phaseto quench NaN₃ with stirring, and NaOH (2 M) was added to mixture toadjust to pH=10. The mixture was allowed to stand overnight. The residuefrom the evaporated organic phase was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1). tert-Butyl(R)-9-amino-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(740 mg, 1.58 mmol, 81% yield) was obtained as a brown oil.

Step 3: ethyl(S)-5-fluoro-12(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate

To a solution of tert-butyl(R)-9-amino-5-fluoro-10-(1-methyl-1H-pyrazol-5-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(740 mg, 1.58 mmol, 1.00 eq) in AcOH (10.0 mL) was added ethyl3-bromo-2-oxo-propanoate (772 mg, 3.96 mmol, 495 uL, 2.50 eq) at 20° C.The mixture was stirred at 120° C. for 6 hr. The reaction mixture wasconcentrated, ethyl acetate (5.00 mL) and water (2.00 mL) were added tothe mixture, followed by saturated NaHCO₃ solution (20.0 mL) to adjustpH to 9. The mixture was extracted with ethyl acetate (10.0 mL*3), thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, Ethyl acetate/MeOH=20/1). ethyl(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate(220 mg, 475 umol, 30% yield) was obtained as a pink solid.

Step 4:(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid

To a solution of ethyl(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate(220 mg, 475 umol, 1.00 eq) in MeOH (8.00 mL) and water (8.00 mL) wasadded NaOH (57.0 mg, 1.42 mmol, 3.00 eq) at 20° C. The mixture wasstirred at 20° C. for 5 h. 1 M HCl (5.00 mL) was added dropwise to thereaction mixture to adjust pH to 3-4. The mixture was concentrated underreduced pressure to afford 470 mg of crude product. 20.0 mg of the crudeproduct was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (0.04% HCl)-ACN]; B %: 25%-55%, 10 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized togive(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid (12.0 mg, 25.4 umol, 99.8% purity, HCl) as a yellow gum. Theremaining batch of the crude product was used in the next step directly.¹H NMR CD₃OD 400 MHz δ=ppm 8.95 (s, 1H), 7.93 (s, 1H), 7.78 (d, J=2.0Hz, 1H), 6.92 (dd, J=10.1, 8.8 Hz, 1H), 6.68 (dd, J=8.7, 3.9 Hz, 1H),6.61 (d, J=2.0 Hz, 1H), 5.20 (d, J=14.5 Hz, 1H), 4.98 (br s, 1H), 4.78(br d, J=6.1 Hz, 1H), 4.63 (t, J=9.4 Hz, 1H), 4.33 (dd, J=9.7, 2.9 Hz,1H), 4.12-4.02 (m, 1H), 3.97-3.88 (m, 1H), 3.79 (s, 3H). LCMS (ESI+):m/z 436.1 (M+H).

Example 136:(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile

To a solution of(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide(180 mg, 414 umol, 1.00 eq) and DIPEA (161 mg, 1.24 mmol, 217 uL, 3.00eq) in DCM (5.00 mL) was added TFAA (174 mg, 829 umol, 115 uL, 2.00 eq)at 0° C. The mixture was stirred at 0° C. for 1 hr under nitrogenatmosphere. The reaction mixture was concentrated. MeOH (2.00 mL) wasadded to the mixture and Na₂CO₃ (8.00 mg) was added to the mixtureadjust pH to 8. LC-MS showed the intermediate was consumed completelyand one peak with the desired mass was detected. The residue wasdissolved in MeOH (3.00 mL). The suspension was filtered, the filtratewas concentrated and purified by prep-HPLC (column: Phenomenex Luna C18200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %: 30%-60%, 8min). The product-containing fraction was concentrated under reducedpressure to remove most of MeCN at 30° C. and the aqueous phase waslyophilized.(S)-5-fluoro-12-(1-methyl-1H-pyrazol-5-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide(13.1 mg, 28.16 umol, 6% yield, 99.4% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHZ δ=ppm 8.88 (s, 1H), 7.52 (s,1H), 7.48 (d, J=1.6 Hz, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.70 (dd, J=8.6,3.7 Hz, 1H), 6.48 (d, J=1.7 Hz, 1H), 4.99-4.90 (m, 1H), 4.85-4.76 (m,1H), 4.59-4.49 (m, 2H), 4.22 (dd, J=9.7, 3.2 Hz, 1H), 4.04 (br s, 1H),3.95-3.84 (m, 1H), 3.76 (s, 3H). LCMS (ESI+): m/z 417.1 (M+H).

Example 137:(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid Step 1: tert-butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a solution of tert-butyl(R)-10-bromo-9-chloro-5-fluoro-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(1.00 g, 2.06 mmol, 1.00 eq) in dioxane (10.0 mL) and water (1.00 mL)were added2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (586mg, 2.68 mmol, 1.30 eq), Pd(dppf)Cl₂ (151 mg, 206 umol, 0.100 eq) andNaHCO₃ (865 mg, 10.3 mmol, 400 uL, 5.00 eq) at 20° C. under nitrogenatmosphere, and the mixture was stirred at 80° C. for 12 h undernitrogen atmosphere. Water (15.0 mL) was added to the reaction solution,the mixture was extracted with ethyl acetate (15.0 mL*3), the combinedorganic layers were dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 0/1). tert-Butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(830 mg, 1.67 mmol, 81% yield) was obtained as a yellow oil.

Step 2: tert-butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate

To a mixture of tert-butyl(R)-9-chloro-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(415 mg, 833 umol, 1.00 eq), NaN₃ (759 mg, 11.7 mmol, 14.0 eq) andsodium ascorbate (198 mg, 1.00 mmol, 1.20 eq) in dioxane (6.00 mL) andwater (1.20 mL) were added CuI (222 mg, 1.17 mmol, 1.40 eq) and(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (237 mg, 1.67 mmol, 2.00eq) at 20° C., then the mixture was stirred at 110° C. for 12 h undernitrogen atmosphere. Saturated NaHCO₃ (25.0 mL) was added to the mixtureto adjust pH to 9, then the mixture was extracted with ethyl acetate(10.0 mL*3), the combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure. NaClO (20 mL, 14%) was addeddropwise to the aqueous phase to quenched NaN₃ under stirring, and themixture was allowed to stand overnight. The organic residue was purifiedby prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1). tert-butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(260 mg, 543 umol, 65% yield) was obtained as a yellow oil.

Step 3: ethyl(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate

To a solution of tert-butyl(R)-9-amino-5-fluoro-10-(2-methylpyridin-3-yl)-13,13a-dihydro-1H-benzofuro[4,3-fg]pyrido[3,2-b][1,4]oxazonine-7(6H)-carboxylate(100 mg, 209 umol, 1.00 eq) in AcOH (3.00 mL) was added ethyl3-bromo-2-oxo-propanoate (102 mg, 522 umol, 65.3 uL, 2.50 eq) at 20° C.The mixture was stirred at 120° C. for 2 h. NaHCO₃ (5%, 8.00 mL) wasadded to the mixture to adjust pH to 7-8, then the mixture was extractedwith ethyl acetate (5.00 mL*3), the combined organic layers were driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by prep-TLC (SiO₂, Ethyl acetate/Methanol=20/1). ethyl(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate(40.0 mg, 84.3 umol, 40% yield) was obtained as a yellow oil.

Step 4:(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid

To a solution of ethyl(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylate(40.0 mg, 84.3 umol, 1.00 eq) in water (2.00 mL) and MeOH (2.00 mL) wasadded NaOH (10.1 mg, 253 umol, 3.00 eq) at 20° C. The mixture wasstirred at 20° C. for 12 h. The reaction was concentrated. Aqueous HCl(1.00 M, 1.50 mL) was added to the mixture to adjust pH to 3-4, and thereaction was concentrated under reduced pressure to afford a crudeproduct (40.0 mg). 20.0 mg of the crude product was purified byprep-HPLC (column: Luna Omega 5 u Polar C18 100 A; mobile phase: [water(0.04% HCl)-ACN]; B %: 16%-34%, 7 min).(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid (7.00 mg, 14.3 umol, 98.4% purity, HCl salt) was obtained as ayellow solid. ¹H NMR DMSO-de 400 MHz δ=ppm 9.03 (s, 1H), 8.83 (d, J=6.0Hz, 1H), 8.48 (br d, J=7.7 Hz, 1H), 8.18 (br s, 1H), 8.01-7.91 (m, 1H),7.73 (s, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 4.97(br dd, J=14.7, 5.2 Hz, 1H), 4.80 (br dd, J=14.0, 5.8 Hz, 1H), 4.55 (brt, J=9.4 Hz, 2H), 4.23 (br dd, J=9.8, 3.2 Hz, 1H), 4.03 (br d, J=9.5 Hz,1H), 3.92-3.83 (m, 1H), 2.59 (s, 3H). LCMS (ESI+): m/z 447.2 (M+H).

Example 138:(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide

To a solution of(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxylicacid (20.0 mg, 44.8 umol, 1.00 eq) in DMF (2.00 mL) was added NH₄Cl(7.19 mg, 134 umol, 3.00 eq), DIPEA (52.1 mg, 403 umol, 70.2 uL, 9.00eq) and HATU (25.6 mg, 67.2 umol, 1.50 eq) at 20° C. The mixture wasstirred at 20° C. for 12 h. The reaction was concentrated. The residuewas purified by prep-HPLC (column: Luna Omega 5 u Polar C18 100 A;mobile phase: [water (0.04% HCl)-ACN]; B %: 17%-35%, 7 min).(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide(6.1 mg, 12.6 umol, 28% yield, 99.6% purity, HCl salt) was obtained as ayellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 8.82 (br d, J=6.0 Hz, 1H),8.68 (br s, 1H), 8.56 (br d, J=7.7 Hz, 1H), 8.02 (t, J=6.8 Hz, 1H), 7.82(s, 1H), 6.89 (t, J=9.5 Hz, 1H), 6.65 (dd, J=3.7, 8.6 Hz, 1H), 5.17 (brd, J=14.8 Hz, 1H), 4.95 (br d, J=14.8 Hz, 1H), 4.72 (d, J=6.0 Hz, 1H),4.60 (t, J=9.2 Hz, 1H), 4.30 (br d, J=8.0 Hz, 1H), 4.06 (br s, 1H),3.98-3.88 (m, 1H), 2.65 (s, 3H). LCMS (ESI+): m/z 446.2 (M+H).

Example 139: General Procedure C for the preparation of(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Step 1: tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Two batches were set up. To tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(21.5 g, 43.8 mmol, 1.00 eq) and (2-methylpyrazol-3-yl)boronic acid(7.16 g, 56.9 mmol, 1.30 eq) in dioxane (50.0 mL) and H₂O (5.00 mL) wasadded Pd(dppf)Cl₂ (3.20 g, 4.38 mmol, 0.100 eq) and Na₂CO₃ (9.28 g, 87.5mmol, 2.00 eq) at 25° C. The mixture was stirred at 80° C. for 12 hrsunder N₂. LC-MS showed tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. Two batches were combined together to work up. The mixture wasfiltered and the filtrate was concentrated under reduce pressure to givea residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 0/1). tert-butyl(S)-12-fluoro-4-(l-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(36.4 g, crude) was obtained as brown solid.

Step 2:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

Three batches were set up. To tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(13.0 g, 26.4 mmol, 1.00 eq) in DCM (108 mL) was added TFA (60.1 g, 527mmol, 39.0 mL, 20.0 eq) at 25° C. The mixture was stirred at 25° C. for12 hrs. LC-MS showed tert-butyl(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. Three batches were combined together to work up. The mixturewas concentrated under reduce pressure to give a residue. Then theresidue was dissolved with EtOAc/H₂O (10.0 mL:10.0 mL). The NH₃.H₂O(25%) was added into the mixture to adjust pH=7.00-8.00, the mixture wasfiltered and the filter cake was dried under reduce pressure.(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(30.0 g, 76.5 mmol, 96.6% yield) was obtained as white solid.

Step 3:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(27.0 g, 68.8 mmol, 1.00 eq) was added i-PrOH (80.0 mL) and H₂O (10.0mL) at 25° C., the mixture was stirred at 80° C. for 1 hr. The mixturewas cooled to 25° C. slowly and stood at 25° C. for 12 hrs. The mixturewas filtered and the filter cake was dried by vacuum to afford 16.0 g ofpure product. The filtrate was concentrated under reduce pressure togive a residue. The residue was purified by reversed-MPLC (neutralcondition). The fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the precipitate was filtered and thefilter cake was dried by vacuum to give 2.00 g of the pure product.Totally 18.0 g of(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazoninewas obtained as white solid.

Step 4:(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(3.50 g, 8.92 mmol, 1.00 eq) in MeCN (60.0 mL) was added MsOH (857 mg,8.92 mmol, 635 uL, 1.00 eq) in MeCN (3.00 mL) dropwise at 50° C., themixture was stirred at 50° C. for 1 hr. The mixture was cooled to 30° C.among 1 hr, the mixture was stirred at 30° C. for 2 hrs. The mixture wascooled to 25° C. The mixture was concentrated under reduced pressure toremove most of MeCN at 30° C., the another batch product (25.0 g, 50.66mmol, 69.02% yield, 99.1% purity, MsOH salt) was combined together andthen H₂O (600 mL) was added into the mixture, the aqueous phase waslyophilized.(S)-12-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(29.1 g, 59.2 mmol, 99.4% purity, MsOH) was obtained as yellow crystal.¹H NMR ET20857-653-P1D CD₃OD 400 MHz δ=ppm 9.51 (s, 1H), 8.03 (s, 1H),7.68 (d, J=1.8 Hz, 1H), 6.92 (t, 7=9.5 Hz, 1H), 6.68 (dd, J=8.8, 3.7 Hz,1H), 6.58 (d, J=1.8 Hz, 1H), 5.20 (d, J=14.8 Hz, 1H), 4.96 (br d, J=14.8Hz, 1H), 4.76 (br dd, J=9.8, 3.9 Hz, 1H), 4.62 (t, J=9.5 Hz, 1H), 4.31(dd, J=9.7, 3.3 Hz, 1H), 4.16-3.99 (m, 1H), 3.98-3.87 (m, 1H), 3.81 (s,3H), 2.70 (s, 4H). LCMS (ESI+): m/z 393.1 (M+H).

Compounds 17, 75, 100, and 171 were prepared according to GeneralProcedure C using the suitable starting materials, precursors,intermediates, and reagents.

Cmpd No. Compound Name Structure Spectral Data 75 (S)-12-fluoro-4-(1-

1H NMR DMSO-d6 400 MHz δ = isopropyl-1H- ppm 9.44 (s, 1H), 7.65 (br t, J= 6.4 pyrazol-5-yl)- Hz, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7a,8,13,14- 7.32(s, 1H), 7.03−6.93 (m, 1H), tetrahydro-7H- 6.71 (dd, J = 8.6, 3.9 Hz,1H), 6.37 [1,2,4]triazolo (d, J = 1.6 Hz, 1H), 4.96−4.88 (m,[4',3':1,6]pyrido[3,2- 1H), 4.83−4.75 (m, 1H), 4.58−4.40 b]benzofuro[4,3- (m. 3H), 4.22 (dd, J = 9.5, 3.5 Hz, fg][1,4] oxanzonine 1H),4.10−4.00 (m, 1H), 3.91−3.81 (m, 1H), 1.34 (dd, J = 8.9, 6.6 Hz, 6h).LCMS (ESI+): m/z 421.2 (M+H) 100 (S)-4-(3-ethyl-1-

¹H NMR DMSO-d₆ 400 MHz δ = methyl-1H-pyrazol- ppm 9.37 (s, 1H), 8.33 (s,1H), 7.33− 4-yl)-12-fluoro- 7.23 (m, 1H), 7.19 (s, 1H), 6.92 7a,8,13,14-(dd, J = 10.1, 8.8 Hz, 1H), 6.66 (dd, tetrahydro-7H- J = 8.5, 3.9 Hz,1H), 4.88−4.81 (m, [1,2,4]triazolo 1H), 4.77−4.69 (m, 1H), 4.53−4.42[4',3':1,6]pyrido[3,2- (m, 2H), 4.21 (dd, J = 9.7, 3.3 Hz, b]benzofuro[4,3-fg] 1H), 4.06−3.96 (m, 1H), 3.89−3.83 [1,4] oxanzonine (m, 1H),3.82 (s, 3H), 2.77 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.4 Hz, 3H). LCMS(ESI+): m/z 421.0 (M+H). 171 (S)-4-(5,6-dihydro-

¹H NMR DMSO-d₆ 400 MHz δ = 4H-pyrrolo[1,2-b] ppm 9.37 (s, 1H), 8.27 (s,1H), 7.27− pyrazol-3-yl)- 7.23 (m, 1H), 7.22 (s, 1H), 6.9312-fluoro-7a,8,13,14- (dd, J = 10.1, 8.8 Hz, 1H), 6.66 (dd,tetrahydro-7H-[1,2,4] J = 8.6, 3.7 Hz, 1H), 4.90−4.79 (m,triazolo[4',3':1,6] 1H), 4.78−4.67 (m, 1H), 4.57−4.42 pyrido[3,2-b] (m,2H), 4.22 (dd, J = 9.6, 3.2 Hz, benzofuro [4,3-fg] 1H), 4.11 (t, J = 7.4Hz, 2H), 4.01 [1,4] oxanzonine (br dd, J = 8.7, 3.6 Hz, 1H), 3.94− 3.83(m, 1H), 3.17 (t, J = 7.3 Hz, 2H), 2.60 (quin, J = 7.2 Hz, 2H). LCMS(ESI+): m/z 419.1 (M+H).

Example 140:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrileStep 1: tert-butyl(S)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up as 10 parallel batches. The solution oftert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(20.0 mg, 28.5 umol, 1.00 eq) and5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (5.30 mg, 28.5 umol, 1.00eq) in dioxane (1.00 mL) was degassed with nitrogen three times.Xphos-Pd-G2 (3.00 mg, 3.81 umol, 1.34e-1 eq) was added at 25° C. and theresulting solution was stirred at 110° C. under nitrogen for 12 h. Thebatches were combined. The obtained mixture was concentrated undervacuum to give a crude product which was purified by prep-TLC(PE:EtOAc=1:2). tert-Butyl(S)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(40.0 mg, 77.3 umol) was obtained as a yellow oil.

Step 2:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile

To a stirred solution of tert-butyl(S)-4-(4-cyano-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(20.0 mg, 38.7 umol, 1.00 eq) in MeOH (1.00 mL) was added HCl/MeOH (4.00M, 1.00 mL) at 15° C. The resulting mixture was stirred at 15° C. for 12h. The mixture was concentrated under reduced pressure and purified byacidic prep-HPLC (FA conditions).(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazole-4-carbonitrile(1.10 mg, 2.25 umol, 5% yield, 94.9% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.49 (s, 1H), 8.15 (s,1H), 8.06-7.94 (m, 1H), 7.67 (s, 1H), 6.98 (t, 7=9.5 Hz, 1H), 6.71 (dd,J=8.8, 3.6 Hz, 1H), 4.99-4.76 (m, 2H), 4.63-4.40 (m, 2H), 4.20 (br dd,J=9.8, 3.2 Hz, 1H), 4.13-3.99 (m, 1H), 3.91-3.73 (m, 1H), 3.81 (s, 3H).LCMS (ESI+): m/z 418.1 (M+H).

Example 141:(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile

Two parallel reactions were set up. To a mixture of(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamide(55.0 mg, 123 umol, 1.00 eq) in DCM (10.0 mL) was addedmethoxycarbonyl-(triethylammonio)sulfonyl-azanide (44.1 mg, 185 umol,1.50 eq) at 0° C., the mixture was stirred at 20° C. for 2 h. LC-MSshowed(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamidewas remained and the desired mass was detected. The mixture was stirredat 20° C. for 12 h, LCMS showed(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carboxamidewas remained and the desired mass was detected. Combined the twobatches. Water (2.00 mL) was added to the mixture, then the reaction wasconcentrated. The residue was dissolved in DMSO (3.00 mL). The solutionwas purified by acidic prep-HPLC (column: Phenomenex Luna C18 200*40mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %: 20%-60%, 8 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized. ¹HNMR showed that the product was not pure, so the product was purified byprep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 25%-60%, 10 min)-ACN]; B %: 20%-60%, 8min). The product-containing fraction was concentrated under reducedpressure to remove most of MeCN at 30° C. and the aqueous phase waslyophilized.(S)-5-fluoro-12-(2-methylpyridin-3-yl)-6,7,15,15a-tetrahydro-1H-benzofuro[4,3-fg]imidazo[1′,2′:1,6]pyrido[3,2-b][1,4]oxazonine-10-carbonitrile(14.0 mg, 32.1 umol, 13% yield, 97.9% purity) was obtained as a yellowsolid. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.57 (br d, J=4.6 Hz, 1H), 8.02 (s,1H), 7.66 (br d, J=7.7 Hz, 1H), 7.22 (dd, J=7.4, 5.0 Hz, 1H), 7.13 (s,1H), 6.90 (t, J=9.4 Hz, 1H), 6.69 (dd, J=8.6, 3.9 Hz, 1H), 5.22-5.06 (m,1H), 4.85 (br d, J=14.7 Hz, 1H), 4.76 (br s, 1H), 4.70-4.60 (m, 2H),4.27 (dd, J=9.7, 2.8 Hz, 1H), 4.00-3.90 (m, 1H), 3.88-3.80 (m, 1H), 2.46(s, 3H). LCMS (ESI+): m/z 428.1 (M+H).

Example 142:(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq),3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (95.7mg, 457 umol, 1.50 eq) and Na₂CO₃ (64.7 mg, 610 umol, 2.00 eq) indioxane (3.00 mL) and water (0.600 mL) was added Pd(dppf)Cl₂ (22.3 mg,30.5 umol, 0.100 eq) at 15° C. under N₂. The resulting mixture wasstirred at 80° C. for 2 h. The mixture was concentrated under reducedpressure. The residue was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) togive tert-butyl(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80 mg, 162 umol, 53% yield) as a yellow solid.

Step 2:(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(70.0 mg, 141.8 umol, 1.00 eq) was added HFIP (2.00 mL) at 15° C. Thesolution was stirred at 80° C. for 12 hr. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase:[water (0.2% FA)-ACN]; B %: 30%-70%, 8 min).(S)-12-fluoro-4-(3-methylisoxazol-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(23.0 mg, 51.9 umol, 36% yield, 99.1% purity, formate salt) was obtainedas a white solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.42 (d, J=7.5 Hz, 1H),7.54 (br t, J=6.2 Hz, 1H), 7.46 (s, 1H), 6.98-6.89 (m, 1H), 6.67 (dd,J=8.7, 3.9 Hz, 1H), 4.93-4.84 (m, 1H), 4.77 (br dd, J=14.8, 6.4 Hz, 1H),4.57-4.44 (m, 2H), 4.21 (br dd, J=9.8, 3.2 Hz, 1H), 4.02-3.97 (m, 1H),3.95-3.85 (m, 1H), 2.50 (s, 3H). ¹H NMR CD₃OD+1 drop HCl (12 M) 400 MHzδ=ppm 9.83 (s, 1H), 8.98 (s, 1H), 8.01 (s, 1H), 6.96-6.86 (m, 1H),6.72-6.65 (m, 1H), 5.15 (d, J=14.9 Hz, 1H), 4.98 (d, J=14.9 Hz, 1H),4.82-4.70 (m, 1H), 4.61 (t, J=9.4 Hz, 1H), 4.32 (dd, J=9.6, 3.1 Hz, 1H),4.17-4.07 (m, 1H), 3.99-3.86 (m, 1H), 2.32 (s, 3H). LCMS (ESI+): m/z394.1 (M+H).

Example 143:(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), (5-fluoro-6-methoxy-3-pyridyl)boronic acid(78.3 mg, 457 umol, 1.50 eq) and KOAc (59.9 mg, 610 umol, 2.00 eq) inEtOH (2.10 mL) and water (0.300 mL) was added4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (21.6mg, 30.5 umol, 21.6 uL, 0.100 eq) at 15° C. under N₂. The resultingmixture was stirred at 80° C. for 2 hr. The mixture was concentratedunder reduced pressure. The mixture was purified by prep-TLC (SiO₂,PE:EtOAc=1:2). tert-Butyl(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 186 umol, 61% yield) was obtained as a yellow solid.

Step 2:(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To tert-butyl(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 167 umol, 1.00 eq) was added HFIP (2.00 mL) at 25° C. Thesolution was stirred at 80° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase:[water (0.2% FA)-ACN]; B %: 45%-65%, 8 min).(S)-12-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(36.1 mg, 72.4 umol, 43% yield, 97.0% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.44 (s, 1H), 8.90 (d,J=2.0 Hz, 1H), 8.51 (dd, J=12.6, 2.0 Hz, 1H), 7.79 (s, 1H), 7.59 (br t,J=6.4 Hz, 1H), 6.93 (dd, J=10.1, 9.0 Hz, 1H), 6.67 (dd, J=8.7, 3.9 Hz,1H), 4.93-4.84 (m, 1H), 4.83-4.73 (m, 1H), 4.58-4.46 (m, 2H), 4.20 (dd,J=9.5, 3.1 Hz, 1H), 4.07-3.99 (m, 1H), 3.98 (s, 3H), 3.97-3.88 (m, 1H).LCMS (ESI+): m/z 438.1 (M+H).

Example 144:(S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-cyclopropyl-6-methylpyrimidin-4-ol

The reaction was set up in two parallel batches. A mixture of methyl3-oxobutanoate (4.81 g, 41.5 mmol, 4.46 mL, 1.00 eq),cyclopropanecarboximidamide hydrochloride (5.00 g, 41.5 mmol, 1.00 eq)and MeONa (14.9 g, 82.9 mmol, 54.4 mL, 30% purity, 2.00 eq) in MeOH (250mL) was stirred at 25° C. for 18 h. The batches were combined. Themixture was diluted with saturated aqueous Na₂SO₃ (250 mL), thenconcentrated under reduced pressure. The residue was dissolved in water(50.0 mL) and adjusted to pH=4 with HCl (2.00 M). The precipitate wasfiltered off and dried under reduced pressure.2-Cyclopropyl-6-methylpyrimidin-4-ol (11.4 g, crude) was obtained aswhite solid.

Step 2: 5-bromo-2-cyclopropyl-6-methylpyrimidin-4-ol

The reaction was set up in two parallel batches. To a solution of2-cyclopropyl-6-methylpyrimidin-4-ol (5.20 g, 34.6 mmol, 1.00 eq) andKOH (1.94 g, 34.6 mmol, 1.00 eq) in water (60.0 mL) was added Br₂ (5.53g, 34.6 mmol, 1.78 mL, 1.00 eq) at 0° C. The mixture was stirred at 30°C. for 18 h. The batches were combined. The precipitate was filtered offand dried under reduced pressure.5-Bromo-2-cyclopropyl-6-methylpyrimidin-4-ol (11.2 g, 48.9 mmol, 70%yield) was obtained as a white solid.

Step 3: 5-bromo-4-chloro-2-cyclopropyl-6-methylpyrimidine

The reaction was set up in two parallel batches. To a mixture of5-bromo-2-cyclopropyl-6-methylpyrimidin-4-ol (2.50 g, 10.9 mmol, 1.00eq) and DMF (1.99 g, 27.3 mmol, 2.10 mL, 2.50 eq) in toluene (100 mL)was added dropwise POCl₃ (2.51 g, 16.4 mmol, 1.52 mL, 1.50 eq) intoluene (25.0 mL) at 0° C., and the mixture was stirred at 30° C. for 3h The batches were combined. The mixture was added to aqueous Na₂CO₃(1.00 M, 150 mL) which was then extracted with EtOAc (50.0 mL*3). Thecombined organic phases were concentrated under reduced pressure.5-Bromo-4-chloro-2-cyclopropyl-6-methylpyrimidine (5.60 g crude) wasobtained as a yellow oil.

Step 4:N′-(5-bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide

The reaction was set up in two parallel batches. A mixture of5-bromo-4-chloro-2-cyclopropyl-6-methylpyrimidine (3.40 g, 13.7 mmol,1.00 eq) and 4-methylbenzenesulfonohydrazide (7.67 g, 41.2 mmol, 3.00eq) in CHCl₃ (300 mL) was stirred at 90° C. for 10 h. The batches werecombined. The precipitate was filtered off, washed with DCM (50.0 mL),and dried under reduced pressure.N′-(5-bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide(6.61 g, crude) was obtained as a white solid.

Step 5: 5-bromo-2-cyclopropyl-4-methylpyrimidine

A mixture ofN′-(5-bromo-2-cyclopropyl-6-methylpyrimidin-4-yl)-4-methylbenzenesulfonohydrazide(6.61 g, 16.6 mmol, 1.00 eq) in aq. Na₂CO₃ (0.56 M, 89.1 mL, 3.00 eq)was stirred at 90° C. for 2 hr. The mixture was extracted with ethylacetate (50.0 mL*3), the combined organic layers were dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1).5-bromo-2-cyclopropyl-4-methylpyrimidine (2.47 g, 11.6 mmol, 69% yield)was obtained as a brown oil.

Step 6: (2-cyclopropyl-4-methylpyrimidin-5-yl)boronic acid

To a solution of 5-bromo-2-cyclopropyl-4-methylpyrimidine (500 mg, 2.35mmol, 1.00 eq) in THF (5.00 mL) was added n-BuLi (2.50 M, 1.03 mL, 1.10eq) at −78° C. under N₂, and the mixture was stirred at −78° C. for 30min. B(OMe)₃ (732 mg, 7.04 mmol, 795 uL, 3.00 eq) was added to themixture at −78° C., and the mixture was stirred at 25° C. under nitrogenfor 5 hr. MeOH (5.00 mL) was added and the mixture was concentratedunder reduced pressure. The residue was purified by reversed phase MPLC(TFA conditions). (2-cyclopropyl-4-methylpyrimidin-5-yl)boronic acid(300 mg, 1.69 mmol, 71% yield) was obtained as a yellow oil.

Step 7:(S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a mixture of (2-cyclopropyl-4-methylpyrimidin-5-yl)boronic acid (150mg, 843 umol, 2.00 eq) and(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(165 mg, 421 umol, 1.00 eq) in dioxane (3.00 mL) and water (0.300 mL)were added Pd(dppf)Cl₂ (30.8 mg, 42.1 umol, 0.100 eq) and Na₂CO₃ (89.3mg, 843 umol, 2.00 eq) at 25° C., the mixture was stirred at 90° C.under nitrogen for 12 hr. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in MeOH(30.0 mL) and silica-thiol (3.00 g, modified silicone gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 6 h. The suspension was filtered and the filtratewas concentrated under reduced pressure. The residue was purified byacidic prep-HPLC (FA conditions), the fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-4-(2-cyclopropyl-4-methylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(12.4 mg, 25.3 umol, 6% yield, 100% purity, formate salt) was obtainedas white solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.31 (s, 1H), 8.46 (s, 1H),7.38 (s, 1H), 6.90-6.83 (m, 1H), 6.63 (dd, J=8.5, 3.9 Hz, 1H), 5.06 (d,J=15.7 Hz, 1H), 4.87 (d, J=15.7 Hz, 1H), 4.57 (t, J=9.3 Hz, 2H),4.30-4.22 (m, 1H), 4.00 (br s, 1H), 3.92-3.83 (m, 1H), 2.34 (s, 3H),2.25-2.18 (m, 1H), 1.15-1.08 (m, 4H). LCMS (ESI+): m/z 445.1 (M+H).

Example 145:(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 6-methylpyridazine 1-oxide and 3-methylpyridazine 1-oxide

To a solution of 3-methylpyridazine (5.00 g, 53.1 mmol, 4.85 mL, 1.00eq) in DCM (100 mL) was added m-CPBA (11.5 g, 53.1 mmol, 80.0% purity,1.00 eq) at 0° C. The mixture was stirred at 20° C. for 2 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by flash silica gelchromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of5-18% EtOH/Petroleum ether gradient @ 40 mL/min). 3-Methylpyridazine1-oxide (1.50 g, 13.6 mmol, 25% yield) with R_(f)=0.38 was obtained as alight yellow gum. 6-Methylpyridazine 1-oxide (2.00 g, 18.2 mmol, 34%yield) with R_(f)=0.43 was obtained as a light yellow solid. A mixtureof 3-methylpyridazine 1-oxide and 6-methylpyridazine 1-oxide (2.50 gcrude) was obtained as a brown gum.

Step 2: 3-methyl-4-nitropyridazine 1-oxide

To a solution of 3-methylpyridazine 1-oxide (4.00 g, 36.3 mmol, 1.00 eq)in H₂SO₄ (45.0 mL) was added HNO₃ (15.9 g, 242 mmol, 11.4 mL, 96.0%purity, 6.67 eq) at 20° C. The mixture was stirred at 90° C. for 5 h.The reaction mixture was poured into ice water (150 mL) at 0° C. andextracted with DCM (50.0 mL*5). The combined organic layers were driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue (˜2.50 g) was purifiedby flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica FlashColumn, Eluent of 50-80% Dichloromethane/Petroleum ether gradient @ 40mL/min). 3-Methyl-4-nitropyridazine 1-oxide (900 mg, 5.80 mmol, 16%yield) was obtained as a yellow gum.

Step 3: 3-methylpyridazin-4-amine

To a solution of 3-methyl-4-nitropyridazine 1-oxide (900 mg, 5.80 mmol,1.00 eq) in MeOH (20.0 mL) was added Raney-Ni (1.00 g) and AcOH (3.15 g,52.5 mmol, 3.00 mL, 9.04 eq) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 20° C. for 12 h. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure to give a crudeproduct. 3-methylpyridazin-4-amine (1.00 g, crude, HO Ac) was obtainedas a green solid.

Step 4: 4-iodo-3-methylpyridazine

To a solution of 3-methylpyridazin-4-amine (1.00 g, 5.91 mmol, 1.00 eq,HOAc) and CH₂I₂ (7.92 g, 29.6 mmol, 2.38 mL, 5.00 eq) in MeCN (30.0 mL)was added isopentyl nitrite (1.52 g, 13.0 mmol, 1.75 mL, 2.20 eq) inMeCN (20.0 mL) at 0° C. under N₂. The reaction mixture was concentratedunder reduced pressure. The residue was purified by flash silica gelchromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of0-50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). 10.0 mL ofdioxane was added to the fraction containing the product. Then themixture was concentrated under reduced pressure until the residualvolume of ˜3 mL (mostly dioxane). 3-methylpyridazin-4-amine (200 mg,1.83 mmol, 31% yield) was recovered as a brown solid. Note: Afterchromatography on silica gel, if the fraction was concentratedcompletely, the product decomposed. The yield was estimated, and thematerial was used a solution in dioxane.

Step 5: tert-butyl(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in 7 parallel batches. A mixture of tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(30.0 mg, 42.8 umol, 1.00 eq), 4-iodo-3-methylpyridazine (18.8 mg, 85.5umol, 2.00 eq), LiCl (2.72 mg, 64.2 umol, 1.31 uL, 1.50 eq), Pd(PPh₃)₄(4.94 mg, 4.28 umol, 0.100 eq) and CuI (4.07 mg, 21.4 umol, 0.500 eq) indioxane (1.50 mL) was degassed and purged with nitrogen 3 times at 25°C., and the mixture was stirred at 80° C. for 2 h under nitrogenatmosphere. The batches were combined. LC-MS showed that tert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas consumed completely and one main peak with desired mass wasdetected. The reaction mixture was concentrated under reduced pressure.The residue was purified by prep-TLC (SiO₂, Ethyl acetate/MeOH=6/1).tert-butyl(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, crude) was obtained as a brown solid.

Step 6:(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A mixture of tert-butyl(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 198 umol, 1.00 eq) in HFIP (3.00 mL) was stirred at 80° C. for12 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (formic acid conditions).(S)-12-fluoro-4-(3-methylpyridazin-4-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(21.1 mg, 51.6 umol, 26% yield, 98.9% purity) was obtained as a brownsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.47 (s, 1H), 9.15 (d, J=5.2 Hz,1H), 7.81-7.71 (m, 2H), 7.55 (s, 1H), 7.02-6.93 (m, 1H), 6.72 (dd,J=8.6, 3.8 Hz, 1H), 4.99-4.89 (m, 1H), 4.87-4.75 (m, 1H), 4.54 (q, J=9.7Hz, 2H), 4.22 (dd, J=9.6, 3.5 Hz, 1H), 4.05 (br s, 1H), 3.94-3.82 (m,1H), 2.60 (s, 3H). LCMS (ESI+): m/z 405.1 (M+H).

Example 146:(S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 2-(triisopropylsilyl)oxazole

The reaction was set up in two parallel batches. To a stirred solutionof oxazole (1.00 g, 14.5 mmol, 926 uL, 1.00 eq) in THF (10.0 mL) wasadded n-BuLi (2.50 M, 6.37 mL, 1.10 eq) at −30° C. under N₂. Theresulting mixture was stirred at −30° C. for 0.5 hr. To the mixture wasadded TIPS-OTf (4.88 g, 15.9 mmol, 4.28 mL, 1.10 eq) at −10° C. underN₂. The resulting mixture was stirred at 15° C. for 12 h. The batcheswere combined. The resulting mixture was quenched by addition ofsaturated aqueous NH₄Cl solution (10.0 mL) and extracted with EtOAc(10.0 mL*3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The mixture was purified by MPLC(SiO₂, PE/EtOAc=1/0 to 1/1) to give 2-(triisopropylsilyl)oxazole (3.00g, 13.3 mmol, 46% yield) as a yellow oil.

Step 2: (2-(triisopropylsilyl)oxazol-5-yl)boronic acid

To the solution of 2-(triisopropylsilyl)oxazole (400 mg, 1.77 mmol, 1.00eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 781 uL, 1.10 eq) dropwiseat −78° C. under N₂. The reaction mixture was stirred at −78° C. for 1hr. Triisopropyl borate (668 mg, 3.55 mmol, 816 uL, 2.00 eq) was addedat −78° C. The mixture was stirred at −78° C. for 1 hr then at 15° C.for 0.5 hr. LCMS indicated complete conversion. MeOH (2.00 mL) wasadded, and the mixture was concentrated under vacuum to give(2-(triisopropylsilyl)oxazol-5-yl)boronic acid (477 mg, crude) as ayellow oil which was used directly in the next step without furtherpurification.

Step 3: tert-butyl(S)-12-fluoro-4-(2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To the solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq) and (2-triisopropylsilyloxazol-5-yl)boronicacid (205 mg, 763 umol, 2.50 eq) in dioxane (6.00 mL) and water (1.00mL) were added KOAc (59.9 mg, 611 umol, 2.00 eq) and Pd(dppf)Cl₂ (22.3mg, 30.5 umol, 0.100 eq). The resulting solution was stirred at 90° C.under nitrogen for 12 h. The mixture was concentrated under vacuum. Thecrude product was purified by prep-TLC (SiO₂, PE:EtOAc=3:2) to obtaintert-butyl(S)-12-fluoro-4-(2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 173 umol, 56% yield) as a yellow oil.

Step 4:(S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To a solution of tert-butyl(S)-12-fluoro-4-(2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 173 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (2.00 mL) at15° C., and the resulting solution was stirred at 15° C. for 2 h. LCMSindicated incomplete conversion. Additional TFA (2.00 mL) was added andthe resulting solution was stirred at 15° C. for 3 h. LCMS showed thatthe reaction was complete. The mixture was concentrated under a nitrogenstream to dryness. The crude product was purified by prep-HPLC (FA) toobtain(S)-12-fluoro-4-(oxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(28.5 mg, 67.0 umol, 38% yield, 100% purity, formate salt) as lightyellow solid. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.92 (s, 1H), 8.12 (s, 1H),7.93 (s, 1H), 7.51 (s, 1H), 6.83 (t, J=9.2 Hz, 1H), 6.65-6.62 (m, 1H),5.24-5.22 (m, 1H), 5.12-5.08 (m, 1H), 4.90-4.85 (m, 1H), 4.67-4.60 (m,2H), 4.28-4.25 (m, 1H), 3.91-3.87 (m, 2H). LCMS (ESI+): m/z 380.1 (M+H).

Example 147:(S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: 4-methyl-2-(triisopropylsilyl)oxazole

To a solution of 4-methyloxazole (1.50 g, 18.1 mmol, 1.00 eq) in THF(20.0 mL) was added n-BuLi (2.50 M, 7.94 mL, 1.10 eq) at −30° C. underN₂. The resulting solution was stirred at −30° C. for 0.5 hr. TIPS-OTf(6.08 g, 19.9 mmol, 5.34 mL, 1.10 eq) was added at −10° C. under N₂ andthe resulting solution was stirred at 25° C. for 12 h. Saturated aqueousNH₄Cl solution (15.0 mL) was added, the mixture was extracted with EtOAc(10.0 mL*3), the combined organic layers were washed with brine (10.0mL), dried over Na₂SO₄, filtered, and under vacuum. The crude productwas purified by column chromatography on basic Al₂O₃ (PE:EtOAc=1:0 to10:1). 4-methyl-2-(triisopropylsilyl)oxazole (3.50 g, 14.6 mmol, 81%yield) was obtained as a yellow oil. ¹H NMR CDCl₃400 MHz δ=ppm 7.49 (s,1H), 2.21 (s, 3H), 1.44-1.36 (m, 3H), 1.12 (d, J=7.6 Hz, 18H).

Step 2: 4-methyl-5-(tributylstannyl)-2-(triisopropylsilyl)oxazole

To the solution of 4-methyl-2-(triisopropylsilyl)oxazole (0.200 g, 835umol, 1.00 eq) in THF (4.00 mL) was added n-BuLi (2.50 M, 368 uL, 1.10eq) dropwise at −78° C. under N₂ and the resulting solution was stirredat −78° C. for 0.5 hr. Tributyl(chloro)stannane (299 mg, 919 umol, 247uL, 1.10 eq) was added at −78° C. and the resulting solution was stirredat −78° C. for 1 hr, then at 15° C. for 2 hr. MeOH (2.00 mL) was addedand the mixture was concentrated under vacuum. The residue was purifiedby prep-TLC (PE:EtOAc=10:1).4-methyl-5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (320 mg, 606umol, 72% yield) was obtained as a colorless oil.

Step 3: tert-butyl(S)-12-fluoro-4-(4-methyl-2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To the solution of4-methyl-5-(tributylstannyl)-2-(triisopropylsilyl)oxazole (194 mg, 366umol, 1.20 eq) in dioxane (5.00 mL) were added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), Pd(PPh₃)₄ (35.3 mg, 30.5 umol, 0.100 eq),LiCl (25.9 mg, 611 umol, 12.5 uL, 2.00 eq) and CuI (23.3 mg, 122 umol,0.400 eq) under N₂. The resulting solution was stirred at 80° C. for 12hr. The mixture was concentrated under vacuum. The residue was purifiedby prep-TLC (PE:EtOAc=1:1). tert-butyl(S)-12-fluoro-4-(4-methyl-2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, 277 umol, 90% yield) was obtained as a yellow oil.

Step 4:(S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

To the solution of tert-butyl(S)-12-fluoro-4-(4-methyl-2-(triisopropylsilyl)oxazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, 277 umol, 1.00 eq) in DCM (1.50 mL) was added TFA (1.50 mL) at15° C. and the resulting solution was stirred at 15° C. for 4 hr. Themixture was concentrated under vacuum. The residue was purified byprep-HPLC (FA) to obtain(S)-12-fluoro-4-(4-methyloxazol-5-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(29.1 mg, 64.7 umol, 23% yield, 97.7% purity, formate salt) as a yellowsolid. ¹H NMR CDCl₃ 400 MHz δ=ppm 8.95 (br s, 1H), 7.93 (s, 1H), 7.32(s, 1H), 6.87 (t, J=9.2 Hz, 1H), 6.69-6.66 (m, 1H), 5.30 (br s, 1H),5.15-5.09 (m, 1H), 4.90-4.86 (m, 1H), 4.68-4.63 (m, 2H), 4.29-4.26 (m,1H), 3.94-3.87 (m, 2H), 2.52 (s, 3H). LCMS (ESI+): m/z 394.1 (M+H).

Example 148:(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonineStep 1: tert-butyl(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL)were added2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(150 mg, 609 umol, 2.00 eq), Na₂CO₃ (64.7 mg, 611 umol, 2.00 eq) andPd(dppf)Cl₂ (22.3 mg, 30.5 umol, 0.100 eq) at 20° C. under nitrogenatmosphere. The mixture was stirred at 80° C. for 12 h under nitrogenatmosphere. The reaction mixture was concentrated. The residue waspurified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate=0/1).tert-butyl(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(260 mg, crude) was obtained as a yellow oil.

Step 2: (S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

A solution of tert-butyl(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(160 mg, 302 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100° C. for2 h. LC-MS indicated incomplete conversion. The mixture was stirred at100° C. for additional 6 h. LC-MS showed that the reaction was complete.The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in DMSO (3.00 mL). The mixture was purified byprep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase:[water (0.2% FA)-ACN]; B %: 30%-60%, 10 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-4-(2-cyclopropylpyrimidin-5-yl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(67.6 mg, 142 umol, 46% yield, 99.5% purity, formate salt) was obtainedas a yellow solid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.47 (s, 1H), 9.39 (s,2H), 7.87 (s, 1H), 7.70 (br t, J=6.1 Hz, 1H), 6.95 (t, J=9.5 Hz, 1H),6.69 (dd, J=8.6, 3.7 Hz, 1H), 4.95-4.75 (m, 2H), 4.58-4.49 (m, 2H), 4.22(br dd, J=9.5, 2.8 Hz, 1H), 4.03 (br d, J=9.2 Hz, 1H), 3.99-3.90 (m,1H), 2.29-2.20 (m, 1H), 1.10-1.02 (m, 4H). LCMS (ESI+): m/z 431.1 (M+H).

Example 149:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-3-amineStep 1:2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-2-methyl-3-nitropyridine (1.00 g, 4.61 mmol,1.00 eq) in dioxane (15.0 mL) were added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.75 g, 6.91 mmol, 1.50 eq), KOAc (905 mg, 9.22 mmol, 2.00 eq) andPd(dppf)Cl₂ (337 mg, 461 umol, 0.100 eq) at 20° C. under nitrogenatmosphere. The mixture was stirred at 80° C. for 12 h under nitrogenatmosphere. Water (10.0 mL) was added to the mixture, the mixture wasextracted with ethyl acetate (8.00 mL*3), the combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 1/1).2-Methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.15 g, 4.35 mmol, 94% yield) was obtained as a white solid.

Step 2:2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

To a solution of2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.15 g, 4.35 mmol, 1.00 eq) in MeOH (25.0 mL) was added 10% Pd/C (2.32g, 50.0% purity) under nitrogen atmosphere. The suspension was degassedand purged with H₂ 5 times. The mixture was stirred under H₂ (15 Psi) at20° C. for 4 h. LC-MS showed2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinewas consumed completely and one main peak with the desired mass wasdetected. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure to give2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(850 mg, crude) as a yellow oil.

Step 3: tert-butyl(S)-4-(5-amino-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(143 mg, 611 umol, 2.00 eq) in water (0.700 mL) and EtOH (4.90 mL) wereadded tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq), KOAc (59.9 mg, 610 umol, 2.00 eq) and4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (21.6mg, 30.5 umol, 21.6 uL, 0.100 eq) at 20° C. under nitrogen atmosphere.The mixture was stirred at 80° C. for 12 hr under nitrogen atmosphere.The reaction mixture was concentrated. The residue was purified byprep-TLC (SiO₂, Ethyl acetate/MeOH=10/1). tert-Butyl(S)-4-(5-amino-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(138 mg, 266 umol, 87% yield) was obtained as a yellow solid.

Step 4:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-3-amine

A solution of tert-butyl(S)-4-(5-amino-6-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 212 umol, 1.00 eq) in HFIP (5.00 mL) was stirred at 100° C. for15 h. The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in DMSO (3.00 mL). The mixture was purified byprep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 10%-40%, 8 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-3-amine(37.3 mg, 89.1 umol, 42% yield, 99.9% purity) was obtained as a yellowsolid. ¹H NMR DMSO-d₆ 400 MHz δ=ppm 9.43 (s, 1H), 8.35 (s, 1H), 7.78 (s,1H), 7.56 (s, 1H), 7.50 (br t, J=6.2 Hz, 1H), 6.95 (t, J=9.5 Hz, 1H),6.68 (dd, J=8.6, 3.7 Hz, 1H), 5.10 (s, 2H), 4.95-4.72 (m, 2H), 4.59-4.47(m, 2H), 4.22 (br dd, J=9.6, 3.0 Hz, 1H), 4.02 (br d, J=8.9 Hz, 1H),3.95-3.87 (m, 1H), 2.31 (s, 3H). LCMS (ESI+): m/z 419.1 (M+H).

Example 150:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-olStep 1:6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol

To a solution of 5-bromo-6-methylpyridin-2-ol (1.00 g, 5.32 mmol, 1.00eq) in dioxane (12.0 mL) were added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.02 g, 7.95 mmol, 1.50 eq), KOAc (1.04 g, 10.6 mmol, 2.00 eq) andPd(dppf)Cl₂ (390 mg, 533 umol, 0.100 eq) at 20° C. under nitrogenatmosphere. The mixture was stirred at 80° C. for 12 hr under nitrogenatmosphere. Water (15.0 mL) was added to the mixture, the mixture wasextracted with ethyl acetate (10.0 mL*3), the combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by MPLC (SiO₂, Petroleum ether/Ethylacetate=1/0 to 1/1).6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol(690 mg, crude) was obtained as a yellow solid.

Step 2: tert-butyl(S)-12-fluoro-4-(6-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(120 mg, 244 umol, 1.00 eq) in dioxane (5.00 mL) and water (0.500 mL)were added6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol(230 mg, 977 umol, 4.00 eq), Na₂CO₃ (51.8 mg, 489 umol, 2.00 eq) andPd(dppf)Cl₂ (17.9 mg, 24.4 umol, 0.100 eq) at 20° C. under nitrogenatmosphere. The mixture was stirred at 80° C. for 12 h under nitrogenatmosphere. LC-MS showed tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas remained and one main peak with the desired mass was detected. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, Ethyl acetate/MeOH=5/1). tert-Butyl(S)-12-fluoro-4-(6-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(95.0 mg, 183 umol, 74% yield) was obtained as a yellow solid.

Step 3:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-ol

To a solution of tert-butyl(S)-12-fluoro-4-(6-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 385 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.0mmol, 2.00 mL, 70.2 eq) at 20° C. The mixture was stirred at 20° C. for1 hr. The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in DMSO (2.00 mL). The mixture was purified byacidic prep-HPLC (column: Luna Omega 5 u Polar C18 100 A; mobile phase:[water (0.04% HCl)-ACN]; B %: 15%-40%, 7 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-ol(104 mg, 228 umol, 59% yield, 100% purity, HCl salt) was obtained as ayellow solid. ¹H NMR CD₃OD 400 MHz δ=ppm 9.53 (s, 1H), 7.94 (s, 1H),7.70 (d, J=9.2 Hz, 1H), 6.98-6.88 (m, 1H), 6.72-6.64 (m, 2H), 5.19 (d,J=14.7 Hz, 1H), 4.95 (br d, J=14.8 Hz, 1H), 4.76 (br dd, J=10.0, 4.3 Hz,1H), 4.63 (t, J=9.5 Hz, 1H), 4.32 (dd, J=9.7, 3.2 Hz, 1H), 4.13-4.05 (m,1H), 3.953-3.85 (m, 1H), 2.25 (s, 3H). LCMS (ESI+): m/z 420.1 (M+H).

Example 151:(S)-12-fluoro-4-(3-methyl-1H-pyrazol-1-yl)-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine

3-Methyl-1H-pyrazole (0.0492 mL, 0.611 mmol) was added to a mixture oftert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(Example 17; 150 mg, 0.305 mmol), K₃PO₄ (130 mg, 0.611 mmol), CuI (5.81mg, 0.0305 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.0193mL, 0.122 mmol) in toluene (0.600 mL) under N₂. The mixture was heatedat 115° C. for 18 h. The mixture was concentrated under reducedpressure. The residue was purified by silica gel chromatography (12.0 gcartridge) eluting with EtOAc in hexanes (0-100%) to afford tert-butyl(S)-12-fluoro-4-(3-methyl-1H-pyrazol-1-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylateas a solid (60 mg, 31%). m/z (ES+) [M+H]⁺: 493.16. HPLC (A05) t_(R)=2.78min.

The solid was diluted with HFIP (3.00 mL) and stirred at 80° C. for 16h. The solution was concentrated under reduced pressure, and the residuewas purified by reverse phase chromatography (BEH C18 30×150ACN/AmBicarb 19 min, 35-55%) to provide the title compound as a solid(5.77 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.96 (d, J=2.1 Hz,1H), 7.72 (s, 1H), 7.42 (t, J=6.0 Hz, 1H), 6.93 (dd, J=10.3, 8.7 Hz,1H), 6.67 (dd, J=8.7, 3.8 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 4.86 (dd,J=14.9, 5.7 Hz, 1H), 4.75 (dd, J=15.3, 6.4 Hz, 1H), 4.58-4.47 (m, 2H),4.24 (dd, J=9.6, 3.5 Hz, 1H), 4.09-3.98 (m, 1H), 3.86 (t, J=11.5 Hz,1H), 2.29 (s, 3H). m/z (ES+) [M+H]⁺: 393.2. HPLC (BEH C18 5-100%ACN/AmForm 10 mM pH4) t_(R)=1.46 min.

Example 152:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpicolinamideStep 1: 5-bromo-N,N-dimethylpicolinamide

To a solution of 5-bromopicolinic acid (1.00 g, 4.95 mmol, 1.00 eq),N-methylmethanamine (484 mg, 5.94 mmol, 1.20 eq, HCl salt) in DMF (10mL) was added DIPEA (1.28 g, 9.90 mmol, 1.72 mL, 2.00 eq) and HATU (2.26g, 5.94 mmol, 1.2 eq) at 25° C. The mixture was stirred at 25° C. for 10h. LCMS showed 5-bromopicolinic acid was consumed completely and theproduct was detected. To the mixture was added water (20 mL), themixture was extracted with EtOAc (20 mL*3). The combined organic layerswere dried over Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by MPLC (SiO₂, PE:EtOAc=1:0 toPE:EtOAc=1:1). 5-Bromo-N,N-dimethylpicolinamide (560 mg, 2.44 mmol, 49%yield) was obtained as a yellow oil.

Step 2:N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide

To a solution of 5-bromo-N,N-dimethylpicolinamide (500 mg, 2.18 mmol,1.00 eq) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(831 mg, 3.27 mmol, 1.50 eq) in dioxane (5.00 mL) was added KOAc (643mg, 6.55 mmol, 3.00 eq) and Pd(dppf)Cl2.DCM (89.1 mg, 109 umol, 0.0500eq) under nitrogen atmosphere at 25° C. The mixture was stirred at 80°C. for 10 h under nitrogen atmosphere. LCMS showed that the reaction wascomplete. The mixture was concentrated under reduced pressure. Theresidue was purified by MPLC (SiO₂, PE:EtOAc=1:0 to EtOAc:MeOH=5:1) togiveN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(100 mg, crude) as a yellow oil.

Step 3:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpicolinamide

To a solution ofN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(74.1 mg, 268 umol, 1.50 eq),(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(70.0 mg, 179 umol, 1.00 eq) and NaHCO3 (75.2 mg, 895 umol, 34.8 uL,5.00 eq) in dioxane (1.00 mL) and water (0.100 mL) was added Pd(dppf)Cl2(13.1 mg, 17.9 umol, 0.100 eq) under nitrogen at 25° C. The resultingmixture was stirred at 80° C. under nitrogen for 3 hr. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in MeOH (2 mL) and silica-thiol (180 mg, modified silicon gelfor eliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andthe mixture was stirred at 20° C. for 3 h. The suspension was filtered,the filtrate was concentrated, and obtained residue was purified byacidic prep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobilephase: [water (0.04% HCl)-ACN]; B %: 20%-50%, 10 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-N,N-dimethylpicolinamide(40.6 mg, 80.56 umol, 45% yield, 98.6% purity, HCl salt) was obtained asa yellow solid. 1H NMR CD3OD 400 MHz δ=ppm 9.62 (s, 1H), 9.00 (br s,1H), 8.41 (br d, J=7.9 Hz, 1H), 8.21 (s, 1H), 7.93 (br d, J=7.8 Hz, 1H),6.90 (t, J=9.5 Hz, 1H), 6.67 (dd, J=8.6, 3.7 Hz, 1H), 5.19 (d, J=14.7Hz, 1H), 5.03-4.94 (m, 1H), 4.85-4.74 (m, 1H), 4.62 (br t, J=9.2 Hz,1H), 4.33 (br d, J=8.6 Hz, 1H), 4.11-4.03 (m, 1H), 4.02-3.94 (m, 1H),3.18 (s, 3H), 3.13 (s, 3H). LCMS (ESI+): m/z 461.2 (M+H).

Example 153:(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)-N-methylpropanamideStep 1: tert-butyl(S,E)-4-(6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of ethyl(E)-3-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylate(678 mg, 2.14 mmol, 3.50 eq) and tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(300 mg, 611 umol, 1.00 eq) in dioxane (8.00 mL) and H₂O (1.60 mL) wereadded Na₂CO₃ (129 mg, 1.22 mmol, 2.00 eq) and Pd(dppf)Cl₂ (44.7 mg, 61.1umol, 0.100 eq) at 15° C. The resulting mixture was stirred at 80° C.for 2 h under N₂. LCMS indicated incomplete conversion. The mixture wasstirred at 80° C. for 12 h. LCMS showed that the reaction was complete.The mixture was concentrated in vacuo. The mixture was purified by MPLC(SiO₂, PE/EtOAc=1/0 to 0/1) to give tert-butyl(S,E)-4-(6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 332 umol, 54% yield) as a yellow oil.

Step 2: tert-butyl(S)-4-(6-(3-ethoxy-3-oxopropyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a stirred solution of tert-butyl(S,E)-4-(6-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(180 mg, 299 umol, 1.00 eq) in MeOH (10.0 mL) was added 10% Pd/C (50.0mg, 50% purity) at 15° C. under N₂. The resulting mixture was stirred at15° C. under H₂ (15 psi) for 12 h. The mixture was filtered and thefiltrate was concentrated in vacuo. tert-Butyl(S)-4-(6-(3-ethoxy-3-oxopropyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, crude) was obtained as a yellow oil.

Step 3:(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)propanoicacid

To a stirred solution of tert-butyl(S)-4-(6-(3-ethoxy-3-oxopropyl)-2-methylpyridin-3-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 248 umol, 1.00 eq) in water (1.00 mL) and MeOH (2.00 mL) wasadded NaOH (19.9 mg, 497 umol, 2.00 eq) at 15° C. The resulting mixturewas stirred at 15° C. for 12 h. The mixture was concentrated in vacuo toremove MeOH. The aqueous phase was acidified with aqueous HCl solution(2.00 M) to pH=23 and the aqueous layer was concentrated in vacuo.(S)-3-(5-(14-(tert-butoxycarbonyl)-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)propanoicacid (130 mg, crude, HCl salt) was obtained as a yellow solid.

Step 4:(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)-N-methylpropanamide

To a stirred solution of(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)propanoicacid (120 mg, 252 umol, 1.00 eq, HCl salt), methanamine hydrochloride(34.1 mg, 505 umol, 2.00 eq) and DIPEA (196 mg, 1.51 mmol, 264 uL, 6.00eq) in DMF (3.00 mL) was added HATU (192 mg, 505 umol, 2.00 eq) at 15°C. The resulting mixture was stirred at 30° C. for 12 h. The mixture waspurified by neutral prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %:10%-40%, 8 min).(S)-3-(5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-2-yl)-N-methylpropanamide(37.7 mg, 75.9 umol, 30% yield, 98.3% purity) was obtained as a yellowsolid. 1H NMR CDCl3 400 MHz δ=ppm 8.88 (s, 1H), 7.63 (d, J=7.9 Hz, 1H),7.11 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.90 (t, J=9.4 Hz, 1H), 6.76 (brs, 1H), 6.69 (dd, J=8.7, 3.9 Hz, 1H), 5.18-5.03 (m, 2H), 4.85 (br dd,J=12.7, 4.0 Hz, 1H), 4.71-4.58 (m, 2H), 4.27 (dd, J=9.7, 3.2 Hz, 1H),4.02-3.91 (m, 1H), 3.88-3.80 (m, 1H), 3.14 (t, J=7.0 Hz, 2H), 2.81 (d,J=4.8 Hz, 3H), 2.68 (t, J=7.0 Hz, 2H), 2.47 (s, 3H). LCMS (ESI+): m/z489.2 (M+H).

Example 154 Step 1: 3-bromo-2-methylpyridin-4-amine

A solution of 2-methylpyridin-4-amine (3.00 g, 27.7 mmol, 1.00 eq) in40.0% HBr (30.0 mL) aqueous solution was stirred at 70° C. and asolution of H₂O₂ (12.6 g, 55.5 mmol, 10.7 mL, 15.0% purity, 2.00 eq) wasadded dropwise over 1 hr period at such a rate that the temperature ofthe reaction mixture remained at 70° C. The mixture was stirred foranother 1 h at 70° C. The mixture was poured on to crushed ice (40.0 g).The pH was adjusted to 7 with solid NaHCO₃. The mixture was extractedwith EtOAc (50.0 mL*3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1/0 to 0/1). 3-Bromo-2-methylpyridin-4-amine (3.00 g, crude) wasobtained as a yellow solid. 1H NMR CD3OD 400 MHz δ=ppm 7.76 (d, J=5.8Hz, 1H), 6.52 (d, J=5.8 Hz, 1H), 2.48 (s, 3H).

Step 2: 3-bromo-2-methylpyridin-4-ol

H₂SO₄ (2.10 g, 21.4 mmol, 1.14 mL, 4.00 eq) (98% purity) and3-bromo-2-methylpyridin-4-amine (1.00 g, 5.35 mmol, 1.00 eq) were addedsuccessively to H₂O (8.00 mL) at 0° C., and then NaNO₂ (553 mg, 8.02mmol, 1.50 eq) in H₂O (8.00 mL) was added dropwise to maintain thetemperature between 0-5° C. After stirring at 15° C. for 1 hr, thereaction mixture was heated at 95° C. for additional 2 h. The mixturewas poured on to crushed ice (20.0 g) and the pH was adjusted to 8 withsolid NaHCO₃. The mixture was concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=1/0 to 0/1 and then Ethylacetate/Methanol=1/0 to 10/1). 3-Bromo-2-methylpyridin-4-ol (1.80 g,crude) was obtained as a yellow solid.

Step 3: tert-butyl(S)-12-fluoro-4-(4-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in two parallel batches. To a solution oftert-butyl(S)-12-fluoro-4-(tributylstannyl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50.0 mg, 71.3 umol, 1.00 eq) in DMF (3.00 mL) were added4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (5.05mg, 7.13 umol, 5.05 uL, 0.100 eq) and 3-bromo-2-methylpyridin-4-ol (26.8mg, 143 umol, 2.00 eq) at 20° C. The mixture was stirred at 110° C. for12 h under N₂. The batches were combined and concentrated under reducedpressure to remove solvent. The residue was purified by prep-TLC (SiO₂,Ethyl acetate/MeOH=5/1). tert-butyl(S)-12-fluoro-4-(4-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, crude) was obtained as a yellow solid.

Step 4:(S)-3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-4-ol

To a solution of tert-butyl(S)-12-fluoro-4-(4-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(80.0 mg, 154 umol, 1.00 eq) in DCM (2.00 mL) was added TFA (0.750 mL)at 20° C. The mixture was stirred at 20° C. for 2 h. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5um; mobile phase: [water (0.04% HCl)-ACN]; B %: 20%-40%, 8 min).(S)-3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-2-methylpyridin-4-ol(28.0 mg, 61.4 umol, 40% yield, 100% purity, HCl salt) was obtained asan off-white solid. 1H NMR CD3OD 400 MHz δ=ppm 9.53 (s, 1H), 8.44 (br s,1H), 8.01 (s, 1H), 7.23 (br dd, J=18.5, 6.6 Hz, 1H), 6.93 (t, J=9.4 Hz,1H), 6.68 (dd, J=8.7, 3.9 Hz, 1H), 5.20 (br dd, J=14.6, 6.4 Hz, 1H),4.98-4.92 (m, 1H), 4.73 (br s, 1H), 4.62 (br t, J=9.5 Hz, 1H), 4.30 (dd,J=9.7, 3.1 Hz, 1H), 4.07 (br s, 1H), 3.89 (br s, 1H), 2.63 (s, 1.5H),2.53 (s, 1.5H). 1H NMR DMSO-d6 400 MHz δ=ppm 14.77 (br s, 1H), 9.77 (s,1H), 8.49 (br s, 1H), 8.44 (d, J=7.2 Hz, 1H), 7.78 (br s, 1H), 7.31 (brs, 1H), 6.99 (t, J=9.6 Hz, 1H), 6.72 (dd, J=8.6, 3.7 Hz, 1H), 5.01-4.91(m, 1H), 4.85 (br s, 1H), 4.59-4.42 (m, 2H), 4.30-4.16 (m, 1H), 4.08 (brs, 1H), 3.83 (br s, 1H), 2.38 (br s, 3H). LCMS (ESI+): m/z 420.2 (M+H).

Example 200 Step 1: 5-bromo-6-methylpyridin-3-amine

To a solution of 3-bromo-2-methyl-5-nitropyridine (5.00 g, 23.0 mmol,1.00 eq) and NH₄Cl (6.25 g, 117 mmol, 5.07 eq) in MeOH (100 mL) and H₂O(100 mL) was added Fe (5.15 g, 92.2 mmol, 4.00 eq) at 25° C., and themixture was stirred at 90° C. for 2 h. LCMS showed that3-bromo-2-methyl-5-nitropyridine was consumed completely and the desiredmass was detected. The mixture was filtered, and the filtrate wasconcentrated under reduced pressure to remove MeOH and then extractedwith EtOAc (50.0 mL*3). The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to give5-bromo-6-methylpyridin-3-amine (3.91 g, crude) as a yellow solid.

Step 2: 5-bromo-6-methylpyridin-3-ol

To a mixture of 5-bromo-6-methylpyridin-3-amine (3.40 g, 18.2 mmol, 1.00eq), trifluoroborane hydrofluoride (21.6 g, 98.3 mmol, 15.3 mL, 40.0%purity, 5.41 eq) and H₂O (15.0 mL) was added drop-wise a solution ofNaNO₂ (1.38 g, 20.0 mmol, 1.10 eq) in H₂O (15.0 mL) at 0° C. The mixturewas stirred at 0° C. for 1 h. Water (15.0 mL) was added to the mixturewhich was then stirred at 100° C. for 12 h. The pH of the mixture wasadjusted with NaHCO₃ to 8. The precipitate was filtered off and driedunder reduced pressure. 5-Bromo-6-methylpyridin-3-ol (3.34 g, crude) wasobtained as a brown solid.

Step 3:6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol

To a solution of 5-bromo-6-methylpyridin-3-ol (3.34 g, 17.8 mmol, 1.00eq) in dioxane (100 mL) was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(6.77 g, 26.7 mmol, 1.50 eq), KOAc (3.49 g, 35.5 mmol, 2.00 eq) andPd(dppf)Cl2 (1.30 g, 1.78 mmol, 0.100 eq) at 25° C. The mixture wasstirred at 100° C. for 12 h under nitrogen. The mixture was concentratedunder reduced pressure to afford a crude product which was used in thenext step directly.6-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol(4.20 g, crude) was obtained as brown solid.

Step 4: tert-butyl(S)-12-fluoro-4-(5-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in 5 parallel batches. To a solution of6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol(120 mg, 509 umol, 5.00 eq) in H₂O (0.300 mL) and dioxane (2.00 mL) wereadded KOAc (20.0 mg, 204 umol, 2.00 eq), tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(50.0 mg, 102 umol, 1.00 eq) and4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (10.8mg, 15.3 umol, 10.8 uL, 0.150 eq) at 25° C., and the mixture was stirredat 90° C. under nitrogen for 12 h. The batches were combined. Theobtained mixture was concentrated under reduced pressure. The residuewas purified by prep-TLC (SiO₂, Ethyl acetate:Methanol=10:1). tert-Butyl(S)-12-fluoro-4-(5-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 385 umol, 76% yield) was obtained as a brown solid.

Step 5:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-3-ol

A solution of tert-butyl(S)-12-fluoro-4-(5-hydroxy-2-methylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(200 mg, 385 umol, 1.00 eq) in HFIP (2.00 mL) was stirred at 100° C. for2 h. The mixture was concentrated under reduced pressure. The residuewas dissolved in MeCN (4.00 mL) and the mixture was purified byprep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase:[water (0.2% FA)-ACN]; B %: 1%-50%, 8 min). The product-containingfraction was concentrated under reduced pressure to remove most of MeCNat 30° C. and the aqueous phase was lyophilized.(S)-5-(12-Fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-6-methylpyridin-3-ol(65.0 mg, 140 umol, 36.3% yield, 100% purity, formate salt) was obtainedas a yellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.42 (s, 1H), 8.15 (s,1H), 8.05 (d, J=2.8 Hz, 1H), 7.49 (br t, J=6.4 Hz, 1H), 7.30 (s, 1H),7.19 (d, J=2.8 Hz, 1H), 7.00-6.94 (m, 1H), 6.70 (dd, J=8.6, 3.9 Hz, 1H),4.97-4.87 (m, 1H), 4.84-4.73 (m, 1H), 4.54 (t, J=9.5 Hz, 1H), 4.47 (brd, J=7.3 Hz, 1H), 4.21 (dd, J=9.7, 3.4 Hz, 1H), 4.09-3.98 (m, 1H),3.91-3.80 (m, 1H), 2.25 (s, 3H). LCMS (ESI+): m/z 420.2 (M+H).

Example 155:(S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)methanolStep 1: 3-(tributylstannyl)picolinaldehyde

The reaction was set up in 2 parallel batches. To the solution ofN,N′,N′-trimethylethane-1,2-diamine (572 mg, 5.60 mmol, 728 uL, 1.20 eq)in THF (10.0 mL) was added n-BuLi (2.50 M, 1.87 mL, 1.00 eq) at −20° C.under nitrogen. The resulting solution was stirred at −20° C. for 15 minfollowed by addition of pyridine-2-carbaldehyde (0.500 g, 4.67 mmol,1.00 eq) was added at −20° C. and the solution was stirred at −20° C.for 15 min. Another portion of n-BuLi (2.50 M, 2.80 mL, 1.50 eq) wasadded at −20° C., the resulting solution was stirred at −20° C. for 0.5hr, and tributyl(chloro)stannane (4.56 g, 14.0 mmol, 3.77 mL, 3.00 eq)was added at −40° C. The reaction mixture was stirred at −40° C. for 1h. The reaction batches were combined, the obtained mixture was pouredinto cold (0° C.) HCl (1.00 M; 10.0 mL), and the mixture was extractedwith EtOAc (20.0 mL*3). The combined organic layers were washed withbrine (10.0 mL), dried over Na₂SO₄, and concentrated under vacuum. Thecrude product was purified by MPLC (PE:EtOAc=1:0 to 10:1).3-(Tributylstannyl)picolinaldehyde (2.20 g, 5.55 mmol, 59.5% yield) wasobtained as a yellow oil which was used directly in the next step.

Step 2: tert-butyl(S)-12-fluoro-4-(2-formylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in 9 parallel batches. To the solution oftert-butyl(S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(100 mg, 204 umol, 1.00 eq) and crude 3-(tributylstannyl)picolinaldehyde(242 mg, 611 umol, 3.00 eq) in dioxane (5.00 mL) was added Pd(t-Bu3P)2(15.6 mg, 30.5 umol, 0.150 eq) and the resulting solution was stirred at120° C. for 12 h under nitrogen. LCMS showed tert-butyl(S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas remained, and the desired ms was detected on LCMS. The parallelreactions were combined and the obtained mixture was concentrated undervacuum. The crude product was purified by prep-TLC (SiO₂,EtOAc:MeOH=10:1). Crude tert-Butyl(S)-12-fluoro-4-(2-formylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylatewas obtained as a brown oil which was used directly in the next step.

Step 3: tert-butyl(S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To the solution of tert-butyl(S)-12-fluoro-4-(2-formylpyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, 213 umol, 1.00 eq) in MeOH (2.00 mL) was added NaBH₄ (9.65 mg,255 umol, 1.20 eq) at 10° C., and the resulting solution was stirred at10° C. for 0.5 h. The mixture solution was concentrated under vacuum togive tert-butyl(S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(110 mg, crude) as a brown oil which was used directly in the next step.

Step 4:(S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)methanol

The solution of tert-butyl(S)-12-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(140 mg, 269 umol, 1.00 eq) in HCl/MeOH (3.00 mL; 4.00 M) was stirred at10° C. for 1 h. The mixture was concentrated under vacuum to give acrude product which was purified by prep-HPLC (column: Phenomenex lunaC18 80*40 mm*3 um; mobile phase: [water (0.04% HCl)-ACN]; B %: 13%-27%).QC indicated insufficient purity and the material was purified byprep-HPLC again (column: Phenomenex luna C18 80*40 mm*3 um; mobilephase: [water (0.04% HCl)-ACN]; B %: 10%-25%) to obtain(S)-(3-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)pyridin-2-yl)methanol(21.4 mg, 45.9 umol, 17% yield, 97.7% purity, HCl salt) as a yellowsolid. 1H NMR CD3OD 400 MHz δ=ppm 9.58 (s, 1H), 8.90 (d, J=6.0 Hz, 1H),8.61 (d, J=7.6 Hz, 1H), 8.16-8.13 (m, 1H), 8.08 (s, 1H), 6.95-6.90 (m,1H), 6.68 (dd, J=8.4, 3.6 Hz, 1H), 5.23-5.19 (m, 1H), 4.98-4.87 (m, 1H),4.87 (s, 2H), 4.77-4.76 (m, 1H), 4.62 (t, J=9.6 Hz, 1H), 4.33-4.29 (m,1H), 4.13-4.10 (m, 1H), 3.95-3.92 (m, 1H). LCMS (ESI+): m/z 420.1 (M+H).

Example 156:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-olStep 1: 1-methyl-1H-pyrazol-4-ol

To a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.00 g, 24.0 mmol, 1.00 eq) in THF (120 mL) were added NaOH (3.00 M,16.0 mL, 2.00 eq) and H₂O₂ (5.45 g, 48.1 mmol, 4.62 mL, 30% purity, 2.00eq) at 0° C., and the mixture was stirred at 0° C. for 3 h. To themixture was added HCl (12.0 M, 3.72 mL) and the mixture was extractedwith a mixture of DCM and MeOH (9:1, 40.0 mL*4). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.1-Methyl-1H-pyrazol-4-ol (5.10 g, crude) was obtained as a yellow oil.

Step 2: 4-(benzyloxy)-1-methyl-1H-pyrazole

To a solution of 1-methyl-1H-pyrazol-4-ol (2.00 g, 20.4 mmol, 1.00 eq)in DMF (20.0 mL) was added NaH (815 mg, 20.4 mmol, 60% purity, 1.00 eq)at 0° C., the mixture was stirred at 25° C. for 30 mins. BnBr (5.23 g,30.6 mmol, 3.63 mL, 1.50 eq) was added to the mixture at 25° C. and themixture was stirred at 25° C. for 2 h. Water (20.0 mL) was added, themixture was extracted with EtOAc (30.0 mL*3), the combined organiclayers were dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1).4-(Benzyloxy)-1-methyl-1H-pyrazole (800 mg, 4.25 mmol, 21% yield) wasobtained as a yellow oil.

Step 3: (4-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)boronic acid

To the solution of 4-(benzyloxy)-1-methyl-1H-pyrazole (750 mg, 3.98mmol, 1.00 eq) in THF (10.0 mL) was added n-BuLi (2.50 M, 1.59 mL, 1.00eq) drop-wise at −78° C. under nitrogen. The reaction mixture wasstirred at −78° C. for 1 hr. Tri-isopropyl borate (749 mg, 3.98 mmol,916 uL, 1.00 eq) was added at −78° C., and the resulting solution wasstirred at −78° C. under nitrogen for 1 hr, and then at 15° C. for 12 h.LCMS indicated incomplete conversion. To the mixture was added n-BuLi(2.50 M, 1.59 mL, 1.00 eq) drop-wise at −78° C. under nitrogen, and theresulting solution was stirred at −78° C. under N2 for 1 hr followed byaddition of tri-isopropyl borate (749 mg, 3.98 mmol, 91.0 uL, 1.00 eq)at −78° C. The reaction mixture was stirred at −78° C. under nitrogenfor 1 hr, then at 15° C. for 12 h. LCMS showed that the conversion wascomplete. MeOH (5.00 mL) was added. The mixture was concentrated underreduced pressure to give (4-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)boronicacid (1.24 g, crude) as a white solid, which was used to the next stepdirectly.

Step 4: tert-butyl(S)-4-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

Two parallel reactions were set up. To a solution of(4-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)boronic acid (354 mg, 1.53 mmol,5.00 eq) in dioxane (5.00 mL) and H₂O (1.00 mL) were added tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(150 mg, 305 umol, 1.00 eq),4-ditert-butylphosphanyl-N,N-dimethyl-aniline dichloropalladium (32.4mg, 45.8 umol, 32.4 uL, 0.150 eq) and KOAc (59.9 mg, 611 umol, 2.00 eq)at 25° C., and the reaction mixture was stirred at 90° C. under N₂ for12 h. The batches were combined. The mixture was concentrated underreduced pressure and the residue was purified by prep-TLC (SiO₂, Ethylacetate:Methanol=20:1). tert-Butyl(S)-4-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(280 mg, crude) was obtained as a yellow solid.

Step 5: tert-butyl(S)-12-fluoro-4-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

To a solution of tert-butyl(S)-4-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(280 mg, 468 umol, 1.00 eq) in MeOH (3.00 mL) was added 10% Pd/C (300mg, 50% purity) under N₂ atmosphere at 25° C. The suspension wasdegassed and purged with hydrogen 3 times. The mixture was stirred underhydrogen (15 Psi) at 40° C. for 1 h. The mixture filtered and thefiltrate was concentrated under reduced pressure to give tert-butyl(S)-12-fluoro-4-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(220 mg, crude) as a yellow solid which was used to the next stepdirectly.

Step 6:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-ol

A solution of tert-butyl(S)-12-fluoro-4-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(220 mg, 432 umol, 1.00 eq) in DCM (1.00 mL) and TFA (1.00 mL) wasstirred at 25° C. for 1.5 h. The mixture was concentrated under reducedpressure. The residue was dissolved in MeCN (4.00 mL) and the mixturewas purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um;mobile phase: [water (0.2% FA)-ACN]; B %: 10%-50%, 8 min). Theproduct-containing fraction was concentrated under reduced pressure toremove most of MeCN at 30° C. and the aqueous phase was lyophilized.(S)-5-(12-Fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-3-ol(50.0 mg, 110 umol, 25.4% yield, 100% purity, formate) was obtained as awhite solid. 1H NMR CD3OD 400 MHz δ=ppm 9.31 (s, 1H), 7.45 (s, 1H), 7.18(s, 1H), 6.87 (t, J=9.6 Hz, 1H), 6.63 (dd, J=8.6, 3.7 Hz, 1H), 5.07 (d,J=14.8 Hz, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.62-4.53 (m, 2H), 4.27 (dd,J=9.7, 3.1 Hz, 1H), 4.05-3.95 (m, 1H), 3.92-3.84 (m, 1H), 3.71 (s, 3H).LCMS (ESI+): m/z 409.1 (M+H).

Example 157:(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one Step 1:4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine

To a solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.00 g, 3.23 mmol, 1.00 eq) in EtOAc (5.00 mL) was added HCl/EtOAc(4.00 M, 10.0 mL, 12.4 eq) at 0° C., the mixture was stirred at 25° C.for 2 h. The reaction was concentrated to afford4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(820 mg, crude, HCl salt) as a white solid.

Step 2:l-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(820 mg, 3.34 mmol, 1.00 eq, HCl) in DCM (12.0 mL) was added DIPEA (1.73g, 13.4 mmol, 2.33 mL, 4.00 eq) and acetyl chloride (393 mg, 5.01 mmol,357 uL, 1.50 eq) at 0° C., and the mixture was stirred at 20° C. for 12h. The reaction was concentrated. The residue was diluted with H₂O (100mL) and extracted with EtOAc (50.0 mL*3). The combined organic layerswere washed with brine (10.0 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure.1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one(850 mg, crude) was obtained as a brown solid.

Step 3:(S)-1-(4-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one

To a solution of(S)-4-bromo-12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine(100 mg, 256 umol, 1.00 eq) in dioxane (2.00 mL) and H₂O (0.200 mL) wereadded1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one(128 mg, 511 umol, 2.00 eq), Na₂CO₃ (54.2 mg, 511 umol, 2.00 eq) andPd(dppf)Cl₂ (18.7 mg, 25.6 umol, 0.100 eq) at 20° C. under N₂, and themixture was stirred at 80° C. for 2 h under N₂ atmosphere. The reactionwas filtered and the filtrate concentrated. The residue was dissolved inMeOH (3.00 mL) and silica-thiol (300 mg, modified silicon gel foreliminating Pd, irregular silica gel, 100-200 mesh, Chlorides (Cl),%≤0.004, particle size distribution 45-75 um) was added at 20° C. andstirred at 20° C. for 12 h. The suspension was filtered and the filtratewas concentrated and purified by acidic prep-HPLC (column: PhenomenexLuna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %:20%-60%, 8 min). The product-containing fraction was concentrated underreduced pressure to remove most of MeCN at 30° C. and the aqueous phasewas lyophilized.(S)-1-(4-(12-Fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one(66.4 mg, 138 umol, 54% yield, 100% purity, formate) was obtained as ayellow solid. 1H NMR DMSO-d6 400 MHz δ=ppm 9.29 (s, 1H), 7.29 (br s,1H), 7.21-7.10 (m, 2H), 6.91-6.84 (m, 1H), 6.62 (dd, J=8.8, 3.9 Hz, 1H),4.91-4.81 (m, 1H), 4.79-4.70 (m, 1H), 4.50 (t, J=9.2 Hz, 1H), 4.43 (dd,J=10.5, 4.4 Hz, 1H), 4.23-4.09 (m, 3H), 3.97 (br d, J=8.8 Hz, 1H),3.89-3.80 (m, 1H), 3.63 (br s, 2H), 2.63 (br s, 2H), 2.02 (s, 3H). LCMS(ESI+): m/z 436.2 (M+H).

Example 158:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-4-olStep 1: 1-methyl-3-((triisopropylsilyl)oxy)-1H-pyrazole

To 1-methyl-1H-pyrazol-3-ol (500 mg, 5.10 mmol, 1.00 eq) and imidazole(694 mg, 10.2 mmol, 2.00 eq) in DCM (10.0 mL) was addedtriisopropylsilyl trifluoromethanesulfonate (2.34 g, 7.65 mmol, 2.05 mL,1.50 eq) at 0° C. The mixture was stirred at 10° C. for 4 h under N₂.The mixture was concentrated under reduce pressure to remove most of DCMand H₂O (3.00 mL) was added. The mixture was extracted with ethylacetate (10.0 mL*3). The combined organic layers were dried withanhydrous Na₂SO₄, filtered, and concentrated under reduce pressure. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=1/0 to 2/1).1-Methyl-3-((triisopropylsilyl)oxy)-1H-pyrazole (1.10 g, 4.32 mmol, 85%yield) was obtained as a colorless oil.

Step 2: 1-methyl-5-(tributylstannyl)-1H-pyrazol-3-ol

To 1-methyl-3-((triisopropylsilyl)oxy)-1H-pyrazole (900 mg, 3.54 mmol,1.00 eq) in THF (3.00 mL) was added t-BuLi (1.30 M, 8.16 mL, 3.00 eq) at−78° C. under N₂. The mixture was stirred at −78° C. for 0.5 hr underN2. Then tributyl(chloro)stannane (3.45 g, 10.6 mmol, 2.85 mL, 3.00 eq)was added into the mixture which was then stirred at −78° C. for 1 hrunder N₂. MeOH (5.00 mL) was added to the mixture and it wasconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1).1-Methyl-5-(tributylstannyl)-1H-pyrazol-3-ol (600 mg, 1.55 mmol, 43.8%yield) was obtained as a colorless oil.

Step 3:1-methyl-5-(tributylstannyl)-3-((triisopropylsilyl)oxy)-1H-pyrazole

To 1-methyl-5-(tributylstannyl)-1H-pyrazol-3-ol (600 mg, 1.55 mmol, 1.00eq) and imidazole (211 mg, 3.10 mmol, 2.00 eq) in DCM (10.0 mL) wasadded triisopropylsilyl trifluoromethanesulfonate (712 mg, 2.32 mmol,625 uL, 1.50 eq) at 0° C. The mixture was stirred at 10° C. for 12 hunder N₂. LC-MS showed minimal conversion. Additional triisopropylsilyltrifluoromethanesulfonate (712 mg, 2.32 mmol, 625 uL, 1.50 eq) was addedto the mixture under N₂, and it was stirred at 10° C. for 12 h. TLC(SiO₂, petroleum ether:ethyl acetate=1:1) indicated complete conversion.The mixture was concentrated under reduce pressure to remove most ofDCM, H₂O (10.0 mL) was added into the mixture which was then extractedwith ethyl acetate (10.0 mL*3). The combined organic layers were driedwith anhydrous Na₂SO₄, filtered, concentrated under reduce pressure.1-Methyl-5-(tributylstannyl)-3-((triisopropylsilyl)oxy)-1H-pyrazole (300mg, crude) was obtained as colorless oil.

Step 4: tert-butyl(S)-12-fluoro-4-(1-methyl-4-((triisopropylsilyl)oxy)-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate

The reaction was set up in two parallel batches. To tert-butyl(S)-4-bromo-12-fluoro-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(40.0 mg, 81.4 umol, 1.00 eq) and1-methyl-5-(tributylstannyl)-3-((triisopropylsilyl)oxy)-1H-pyrazole(66.4 mg, 122 umol, 1.50 eq) in dioxane (1.00 mL) were added Pd(PPh3)4(9.41 mg, 8.14 umol, 0.100 eq), LiCl (6.90 mg, 163 umol, 3.33 uL, 2.00eq) and CuI (6.20 mg, 32.6 umol, 0.400 eq) at 10° C. The mixture wasstirred at 100° C. for 12 h under N₂. The batches were combined. Theobtained mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=1/3). tert-Butyl(S)-12-fluoro-4-(1-methyl-4-((triisopropylsilyl)oxy)-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(90.0 mg, 135 umol, 83% yield) was obtained as a yellow oil.

Step 5:(S)-5-(12-fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-4-ol

To tert-butyl(S)-12-fluoro-4-(1-methyl-4-((triisopropylsilyl)oxy)-1H-pyrazol-5-yl)-7a,13-dihydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonine-14(8H)-carboxylate(155 mg, 233 umol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.54 g, 13.5mmol, 1.00 mL, 57.9 eq) at 10° C. The mixture was stirred at 10° C. for2 h. The mixture was concentrated under reduce pressure to give aresidue. The crude product was purified by prep-HPLC (HCl conditions).(S)-5-(12-Fluoro-7a,8,13,14-tetrahydro-7H-[1,2,4]triazolo[4′,3′:1,6]pyrido[3,2-b]benzofuro[4,3-fg][1,4]oxazonin-4-yl)-1-methyl-1H-pyrazol-4-ol(40.3 mg, 90.2 umol, 39% yield, 99.6% purity, HCl salt) was obtained asa yellow solid. 1H NMR CD3OD 400 MHz δ=ppm 9.51 (s, 1H), 8.02 (s, 1H),6.92 (dd, J=10.1, 8.8 Hz, 1H), 6.68 (dd, J=8.7, 3.9 Hz, 1H), 5.90 (s,1H), 5.20 (d, J=14.8 Hz, 1H), 4.95 (br d, J=14.8 Hz, 1H), 4.76 (br dd,J=9.6, 3.9 Hz, 1H), 4.62 (t, J=9.4 Hz, 1H), 4.31 (dd, J=9.8, 3.4 Hz,1H), 4.11-4.00 (m, 1H), 3.97-3.85 (m, 1H), 3.61 (s, 3H) LCMS (ESI+): m/z409.1 (M+H)

Example 159: Histone Methyltransferase Assay

Effect of compounds of the present disclosure on EZH2/PRC2 complexmethyltransferase functional activity was measured using theradioisotope-based HotSpot assay described by Horiuchi, K. Y., et al.Assay Drug Dev Technol. 11(4):227-36 (2013). Briefly, compounds wereprepared in a 10-point 3-fold serial dilution in DMSO from a 10 mM stockin ECHO qualified plate using Assist Plus (Integra Biosciences) liquidhandler. Four microliters of EZH2/PRC2 complex (12.5 nM) and corehistone substrate (0.0625 mg/mL) mix in assay buffer (50 mM Tris-HCl (pH8.0), 0.01% Brij35, 1 mM EDTA, 1 mM DTT, 1% DMSO) were transferred intoa 384-well assay plate by hand. Nanoliter quantities of each compound'sconcentration series were transferred into the enzyme/substrate mixusing (Echo 550, LabCyte Inc. Sunnyvale, Calif.) acoustic dispenser andpre-incubated for 20 min at room temperature. The methylation reactionwas initiated by the addition of 1 μl of 5 μMS-Adenosyl-L-[methyl-³H]methionine (³H-SAM) and incubated at 30° C. for1 h. The final concentration of the EZH2/PRC2 complex, core histonesubstrate and ³H-SAM were 10 nM, 0.05 mg/ml, and 1 μM respectively. The% activity of test samples were calculated with reference to positive(no compound) and negative (no EZH2/PRC2) controls on the plate usingExcel (Microsoft). The resulting values were exported to Prism (GraphPadsoftware) to generate concentration response curves and IC₅₀ valuesusing the four-parameter logistic equation.

Example 160: EED Binding SPR Assay Biotinylated EED Protein Production

Biotinylated AVI-tagged EED was produced using standard molecularbiology techniques. A pGEX plasmid with aGST-preScission-cleavage-site-AVI-EED(76-441) sequence was placed intoE. coli BL21(DE3) cells and co-expressed with pGro7. The E. coli weregrown in shaker flasks in LB with ampicillin at 37° C. at 110 rpm to anOD₆₀₀=0.7. At this time the temperature was lowered to 15° C. and IPTGwas added to 0.3 mM. The cells were allowed to express overnight. Cellswere then harvested.

For purification, the E. coli cell pellet was lysed into a buffer of 50mM Tris pH 8.0, 500 mM NaCl, 5% glycerol and 5 mM DTT. The lysate wasloaded onto a GSTrap FF column from GE Healthcare. After washing, thebound protein was eluted with 50 mM Tris pH 8.0, 500 mM NaCl, 5%glycerol, 5 mM DTT and 15 mM GSH. The collected fractions were combinedand incubated with PreScission enzyme overnight at 4° C. The cleavedprotein was then passed through a GSTrap FF column in a buffer of 50 mMTris pH 8.0, 500 mM NaCl, 5% glycerol and 5 mM DTT. The cleaved proteinwas confirmed through mass spectrometry. The AVI-EED(76-441) was thenbuffer exchanged into 50 mM Bicine pH 8.3, 10 mM ATP, 10 mM magnesiumacetate and 50 μM D-Biotin. 3 mg of BirA enzyme was added to the systemand incubated at 4° C. for 2 hours to biotinylate the AVI-EED(76-441).The biotinylated-AVI-EED(76-441) was then buffer exchanged into 20 mMTris pH 8.0 and 400 mM NaCl and passed through a size exclusion columnof Superdex 200 16/60 Increase. The purified monomericbiotinylated-AVI-EED(76-441) was confirmed through SDS-PAGE, LC-MS andanalytical size exclusion chromatography.

Surface Plasmon Resonance Assay

All surface plasmon resonance (SPR) assays were performed using a GEBiacore S200 utilizing GE Biotin CAPture chips. Capturing of CAPreagents was performed with a flow rate of 2 μL/min for 90 seconds. Forprotein capturing, a solution of 50 μg/mL of biotinylated AVI-tagged EED(76-441) in 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween 20 and 2% DMSO(Running Buffer) was flowed over the chip with a flow rate of 5 μL/minfor a contact time of 30 seconds. Final readings were 2200-2400 RU. Forcompounds, 7 concentrations were made with 3-dilutions using the RunningBuffer for a total of 300 μL of each concentration in a 96-wellmicroplate. During the binding experiments, a flow rate of 50 μL wasused for an association time of 90 seconds followed by a disassociationtime of 180 seconds. The compartment temperature was set at 10° C. withthe chip at 25° C. During regeneration the flow rate was set to 30μL/min for 30 seconds. All fittings were done using a 1:1 binding model.

Example 161: H3K27me3 and HbF Immunocytochemistry Assay and HemoglobinELISA Assay Generation of a P-gp Expressing HEK293T Cell Line

A plasmid encoding the human ABCB1 gene under the control of a CMVpromoter was purchased from Origene (Cat #RC216080). The HEK293T cellswere purchased from ATCC (Cat #CRL-3216) and were cultured for expansionin the recommended conditions. The HEK293T cells were transfected with 2ug of the pCMV-ABCB1 plasmid using Lipofectamine 3000 followingrecommendations from the manufacturer (ThermoFisher Scientific, Cat#L3000008). After 24 h, cells were dissociated, and 5000 cells wereseeded on a 10 cm tissue culture dish. On the next day, fresh mediacontaining 5 nM Vinblastine (Sigma, Cat #V1377) was added, and mediacontaining compound was replenished every 72 h. After surviving cellsreached confluency, cells were passaged, and lines were maintained inthe presence of 2.5 nM Vinblastine until further characterization.

Tissue Culture

P-gp expressing HEK293T, HUDEP2, and Human Mobilized Peripheral BloodPrimary CD34+ cells were cultured for use in an H3K27me3immunocytochemistry assay. HUDEP2 and Human Mobilized Peripheral BloodPrimary CD34+ cells were cultured for use in an HbF immunocytochemistryassay. P-gp expressing HEK293T cells were maintained and passaged every3-4 days by plating 300,000 viable cells in a T-25 culture flaskcontaining 6 mLs of 293 Passaging Media comprised of DMEM (ThermoFisher#10566016), 10% fetal bovine serum (ThermoFisher #A3160502), 1%penicillin-streptomycin (ThermoFisher #15140122), and 2.5 nM Vinblastine(Sigma #V1377). To evaluate the inhibitory effect of the compounds ofthe present disclosure and their brain penetrant properties via P-gpmediated efflux, the H3K27me3 immunocytochemistry assay was conducted inthe presence or absence of 250 nM of the P-gp inhibitor, elacridar. Poorbrain penetrant compounds were expected to show higher potencies in thepresence of Elacridar. However, brain penetrant compounds would showsimilar potencies irrespective of whether Elacridar is present or not.In these experiments plates without elacridar were seeded with P-gpexpressing HEK293T cells at 1000 viable cells per well in apoly-d-lysine coated 384-well plate (Corning Cat #356697) in 45 μL of293 Assay Media comprised of DMEM (ThermoFisher #10566016), 10% fetalbovine serum (ThermoFisher #A3160502), 1% penicillin-streptomycin(ThermoFisher #15140122). A replicate set of plates were seeded underthe same conditions with 45 μL of 293 Assay Media supplemented with 250nM of Elacridar to inhibit P-gp activity. Compounds were seriallydiluted at 10× concentration in 293 Media, and 5 μL transferred to theirrespective wells on both sets of plates for a total volume of 50 μL perwell. The compound treated HEK293T cells were allowed to incubate for 4days at 37° C., 85% relative humidity, and 5% CO₂ before proceeding toICC Fix and Stain protocol.

HUDEP2 cells were maintained and passaged every 2-3 days by seeding300,000 viable cells/mL in a culture flask containing HUDEP2 GrowthMedia comprised of StemSpan SFEM (Stemcell Technologies #09650), 50ng/mL human stem cell factor (Stemcell Technologies #78062.2), 3 IU/mLerythropoietin (ThermoFisher #PHC2054), 1 μM dexamethasone (Sigma#D2915), and 1 pg/mL doxycycline (Sigma #D3072). HUDEP2 cells weredifferentiated towards erythroid lineage by seeding at 25,000 viablecells/well in 96-well V-Bottom plates (Corning #3894) containing 135 μLHUDEP2 Differentiation Media comprised of Iscove's Modified Dulbecco'sMedium (Stemcell Technologies #36150), 1% L-glutamine (ThermoFisher#25030081), 2% penicillin-streptomycin (ThermoFisher #15140122), 330μg/mL holo-human transferrin (Sigma #T0665), 2 IU/mL heparin (StemcellTechnologies #07980), 10 μg/mL recombinant human insulin (Sigma#91077C), 3 IU/mL erythropoietin (ThermoFisher #PHC2054), 100 ng/mLhuman stem cell factor (Stemcell Technologies #78062.2), and 4% fetalbovine serum (ThermoFisher #A3160502). Chemical probes for treatmentwere resuspended in 100 μL of Iscove's Modified Dulbecco's Medium(Stemcell Technologies #36150) to a 10× concentration, and 15 μL of 10×concentrated chemical probes were added to each well for a total wellvolume of 150 μL. HUDEP2 cells were left to incubate at 37° C., 85%relative humidity, and 5% CO₂ for 3 days. On Day 3, assay platescontaining HUDEP2 cells were centrifuged at 500×g for 5 minutes. Aftercentrifugation cells were pelleted to the bottom of the well, and 100 μLof media aspirated from the well without disturbing the cells. Then 90μL of fresh HUDEP2 Differentiation Media and 10 μL of 10× concentratedchemical probes were added back each well. For the H3K27me3 assay, cellswere harvested on Day 4 of treatment. The HUDEP2 cells were centrifugedat 500×g for 5 minutes and all media was aspirated from the well. Then150 μL of phosphate buffered saline (ThermoFisher #10010023) was addedto each well to resuspend the cells. Finally, 50 μL of the HUDEP2 cellsuspension from each well was transferred to a poly-d-lysine coated384-well plate (Corning Cat #356697) and centrifuged at 1000×g for 5minutes before proceeding to ICC Fix and Stain Protocol. Assay platesfor the HbF assay were returned to the incubator until Day 5, where themedia was exchanged and chemical probes added exactly as on Day 3. OnDay 7 of the HbF assay, the HUDEP2 cells were harvested in the samemanner as described for the H3K27me3 assay before proceeding to ICC Fixand Stain Protocol.

Human Mobilized Peripheral Blood Primary CD34+ cells were expanded fromthaw by seeding 100,000 viable cells/mL in a culture flask containingCD34+ Expansion Media comprised of StemSpan SFEMII (StemcellTechnologies #09655), 1% erythroid expansion supplement (StemcellTechnologies #02692), and 1 μM dexamethasone (Sigma #D2915). The cellswere supplemented by adding an additional IX culture volume of CD34+Expansion Media on Day 3 after thaw. After 7 days of expansion, PrimaryCD34+ cells were differentiated towards erythroid lineage by seeding at15,000 viable cells/well in 96-well V-Bottom plates (Corning #3894)containing 135 μL CD34+ Differentiation Media comprised of StemSpanSFEMII (Stemcell Technologies #09655), 3% normal human serum (Sigma#H4522), 3 IU/mL erythropoietin (ThermFisher #PHC2054). Chemical probesfor treatment were resuspended in 100 μL of Iscove's Modified Dulbecco'sMedium (Stemcell Technologies #36150) to a 10× concentration, and 15 μLof 10× concentrated chemical probe was added to each well for a totalwell volume of 150 μL. Primary CD34+ cells were left to incubate at 37°C., 85% relative humidity, and 5% C02 for 3 days. On Day 3, assay platescontaining Primary CD34+ cells were centrifuged at 500×g for 5 minutes.After centrifugation cells were pelleted to the bottom of the well, and100 μL of media aspirated from the well without disturbing the cells.Then 90 μL of fresh CD34+ Differentiation Media and 10 μL of 10×concentrated chemical probes were added back each well. For the H3K27me3assay, cells were harvested on Day 4 of treatment. The Primary CD34+cells were centrifuged at 500×g for 5 minutes and all media wasaspirated from the well. Then 150 μL of phosphate buffered saline(ThermoFisher #10010023) was added to each well to resuspend the cells.Finally, 50 μL of the Primary CD34+ cell suspension from each well wastransferred to a poly-d-lysine coated 384-well plate (Corning Cat#356697) and centrifuged at 1000×g for 5 minutes before proceeding toICC Fix and Stain Protocol. Assay plates for the HbF assay were returnedto the incubator until Day 5, where the media was exchanged and chemicalprobes added exactly as on Day 3. On Day 7 of the HbF assay, the PrimaryCD34+ cells were harvested in the same manner as described for theH3K27me3 assay before proceeding to ICC Fix and Stain Protocol.

The Fix and Stain Protocol was the same for HEK293T, HUDEP2, and PrimaryCD34+ cell assays except the specific primary and secondary antibodiesused for detection. Following 4 days of compound treatment, therespective plates were washed once with 25 μL of PBS (ThermoFisher#10010023) and fixed with 25 μL of 4% paraformaldehyde (ThermoFisher#28908) for 10 minutes at room temperature. The plates were then washedthree times with 25 μL of PBS. Subsequent to that, the cells werepermeabilized and blocked for 1 hour at room temperature in 25 μL ofPerm/Block buffer comprised of IX PBS, 1% bovine serum albumin(ThermoFisher #A3294), 10% fetal bovine serum (ThermoFisher #A3160502),0.3M glycine (Sigma #G7126), and 0.1% tween-20 (Sigma #P7949). This wasfollowed by additional washing (three times) of the plates with 25 μL of0.1% tween in PBS.

For the H3K27me3 assay, the cells were incubated overnight at 4° C. with25 μL of H3K27me3 Primary Antibody (Cell Signaling #9733) diluted 1:200in 0.1% tween-20 in PBS. On the next day, the cells were washed againthree times with 25 μL of 0.1% tween-20 in PBS and incubated at roomtemperature in the dark for 1 hour with 25 μL Secondary AntibodySolution comprised of Donkey Anti-Rabbit 488 (ThermoFisher #A21206) andHoechst (ThermoFisher #H3570) diluted 1:2000 in 0.1% tween in PBS.Finally, the cells were washed three times with 25 μL of PBS and sealedwith a foil (BioRad #MSB1001) for imaging on the ThermoFisherCellInsight CX7.

Plates for the HbF assay were treated similarly as described aboveexcept that HbF Primary Antibody (ThermoFisher #MHFH01-4) diluted 1:40in 0.1% tween-20 in PBS and Hoescht (ThermoFisher #H3570) diluted 1:2000in 0.1% tween-20 in PBS were used for detection.

H3K27me3 and HbF Immunocytochemistry Assay

The plates were then scanned on the CX7 at 10× magnification, and 9images were acquired per well. The software algorithm then identifiednuclei and calculated a total nuclei count using the Hoechst staining onchannel 1. After nuclei were identified, the algorithm calculated theaverage nuclear intensity of the H3K27me3 or HbF staining on channel 2.Data for total nuclei count was reported as a percentage of negativecontrol (% DMSO). Data for average nuclear intensity of H3K27me3 or HbFwas reported as a controls normalized percent inhibition((σ_(Pos)−Sample_(i)/σ_(Pos)−σ_(Neg))*100). A threshold for HbFpositivity was set and HbF data was also reported at % HbF+ out of totalnumber of cells.

Hemoglobin ELISA Assay

HUDEP2 cells were cultured as described above. Briefly, 100,000 cellswere grown in differentiation media and treated with compound for 7 dayswith media and compound changed on Day 3 and Day 5. Cells were pelletedby centrifugation (900×g for 5 minutes), resuspended in 100 uL of lysisbuffer (50 mM Tris buffered saline, pH8.0; 0.05% Tween 20 (SigmaChemical #T9039) to generate cell lysates and frozen at −80 C. The celllysates were analyzed for protein content per well using bicinchoninicacid (BCA) assay (Pierce BCA kit #23225), total hemoglobin content perwell using enzyme-linked immunosorbent (ELISA) assays (BethylLaboratories #E80-134) and fetal hemoglobin (HbF) content per well usingELISA assays (Bethyl Laboratories #E80-136).

BCA assays were run to calculate the total protein content and determinethe amount of lysate to load onto the total hemoglobin and HbF assays.In general, 100 uL of BCA buffer was added to a well of a clear 96-wellplate. 2 uL of cell lysate was loaded to the well. Sample was incubatedat 37 degrees Celsius for 30 minutes and analyzed on an Envision platereader (PerkinElmer). Protein content was calculated using bovine serumalbumin as a standard.

Total hemoglobin and HbF ELISA assays were performed following theprotocol recommended by the manufacturer. In general, each sample wasanalyzed for total hemoglobin and HbF content. 1 μl of affinity purifiedantibody (Total hemoglobin: A80-134A, HbF: A80-136A) to 100 μl CoatingBuffer (0.05M carbonate-bicarbonate in water) for each well to be coated(example: for 100 wells dilute 100 μl to 10 ml) in the ELISA plates.Plates were incubated at room temperature for 60 minutes. The well wasthen washed 5 times with 100 uL of wash buffer (50 mM Tris bufferedsaline, pH8.0; 0.05% Tween 20). 200 uL of blocking buffer (50 mM Trisbuffered saline, pH8.0; 1% bovine serum albumin) was added to each welland incubated for 1 hour at room temperature. The well was then washed 5times with 100 uL of wash buffer. Cell lysates were diluted in 50 mMTris buffered saline, pH8.0; 0.05% Tween 20; 1% bovine serum albumin andthe appropriate amount of material was added to be within the linearrange of the total hemoglobin or HbF standard curve (Total hemoglobincalibrator: Bethyl RC80-135-5; Fetal hemoglobin calibrator: BethylRC80-135-5). Samples were incubated at room temperature for 1 hour withshaking (300 rpm). The well was then washed 5 times with 100 uL of washbuffer. Detection antibody (Total hemoglobin: A80-134P and HbF:A80-136P) was diluted 1:100,000 in 50 mM Tris buffered saline, pH8.0;0.05% Tween 20; 1% bovine serum albumin and 100 uL was added percorresponding well. Samples were incubated for 1 hour at roomtemperature with shaking (300 rpm). The well was then washed 5 timeswith 100 uL of wash buffer. 100 uL of TMB One Component HRP reagent wasadded to the well and incubated for 15 minutes in the dark at roomtemperature. 100 uL of stop solution (Bethyl Laboratories #E115) wasthen added to each well, directly into the TMB solution. The absorbancewas measured on an Envision plate reader at 450 nm.

Table 2 below describes inhibitory effects of compounds of Formula I onthe HMT enzyme where “+++++” indicates a measured IC₅₀ value <0.025 μM;“++++” indicates a measured IC₅₀ value from 0.025 μM to 0.050 μM of thedisclosed compound; “+++” indicates a measured IC₅₀ value from 0.050 μMto 0.10 μM of the disclosed compound; “++” indicates a measured IC₅₀value from 0.10 μM to 0.50 μM of the disclosed compound; and “+”indicates a measured IC₅₀ value >0.50 μM of the disclosed compound.

TABLE 2 Compounds with Compounds with Compounds with Compounds withCompounds with an IC₅₀ an IC₅₀ value from an IC₅₀ value from an IC₅₀value from an IC₅₀ value <0.025 μM 0.025 μM to 0.050 μM 0.050 μM to 0.10μM 0.10 μM to 0.50 μM value >0.50 μM 1, 3, 4, 7, 8, 9, 10, 5, 26, 176 1411 6, 185, 198 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 48, 49,51, 53, 57, 59, 60, 62, 63, 68, 69, 70, 71, 72, 85, 86, 89, 94, 102,115, 121, 125, 126, 130, 131, 132, 133, 145, 146, 157, 164, 165, 167,168, 169, 172, 175, 186, 189

Table 3 below describes the equilibrium dissociation constant (Ku) asmeasured by surface plasmon resonance (SPR) of compounds of Formula Iwhere “+++++” indicates a measured Ku concentration <0.0025 μM; “++++”indicates a measured Ku concentration from 0.0025 μM to 0.0050 μM of thedisclosed compound; “+++” indicates a measured Ku concentration from0.0050 μM to 0.010 μM of the disclosed compound; “++” indicates ameasured Ku concentration from 0.010 μM to 0.050 μM of the disclosedcompound; and “+” indicates a measured Ku concentration >0.050 μM of thedisclosed compound.

TABLE 3 Compounds with Compounds with Compounds with Compounds withCompounds with an K_(D) an K_(D) value from an K_(D) value from an K_(D)value from an K_(D) value <0.0025 μM 0.0025 μM to 0.0050 μM 0.0050 μM to0.010 μM 0.010 μM to 0.050 μM value >0.050 μM 1, 3, 8, 9, 13, 15, 16,12, 21, 24, 37, 38, 5, 10, 25, 78, 79, 83, 4, 7, 14, 26, 39, 65, 6, 11,140 17, 18, 19, 20, 22, 46, 48, 55, 56, 64, 105, 122, 143, 161, 98, 101,107, 113, 23, 27, 28, 29, 30, 74, 81, 82, 110, 111, 174 120, 121, 138,141, 31, 32, 33, 34, 35, 112, 136, 142, 144, 149, 159, 165, 176, 36, 40,41, 42, 43, 150, 153, 154, 162, 177, 192, 197 44, 45, 47, 49, 50, 16651, 52, 53, 54, 57, 58, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 72,73, 75, 76, 77, 80, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 99, 100, 102, 103, 104, 106, 108, 109, 114, 115, 116, 117, 118, 119,123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137,139, 145, 146, 147, 148, 151, 152, 155, 156, 157, 158, 160, 163, 164,167, 168, 169, 170, 171, 172, 175, 178, 179, 186, 187, 188, 189, 190,191, 193, 194, 195, 196, 197

Table 4 below describes inhibitory activity of compounds of Formula I onhuman P-glycoprotein HEK cells (HEK-P-gp) where “+++++” indicates ameasured IC₅₀ value <0.025 μM; “++++” indicates a measured IC₅₀ valuefrom 0.025 μM to 0.050 μM of the disclosed compound; “+++” indicates ameasured IC₅₀ value from 0.050 μM to 0.10 μM of the disclosed compound;“++” indicates a measured IC₅₀ value from 0.10 μM to 0.50 μM of thedisclosed compound; and “+” indicates a measured IC₅₀ value >0.50 μM ofthe disclosed compound.

TABLE 4 Compounds with Compounds with Compounds with Compounds withCompounds with an IC₅₀ an IC₅₀ value from an IC₅₀ value from an IC₅₀value from an IC₅₀ value <0.025 μM 0.025 μM to 0.050 μM 0.050 μM to 0.10μM 0.10 μM to 0.50 μM value >0.50 μM 8, 17, 18, 19, 23, 13, 15, 40, 49,50, 12, 20, 21, 27, 28, 1, 16, 22, 39, 41, 3, 4, 5, 6, 7 , 9, 10, 29,32, 33, 34, 35, 53, 62, 66, 80, 86, 30, 31, 38, 44, 46, 45, 47, 52, 55,63, 11, 14, 24, 25, 26, 36, 42, 43, 57, 69, 87, 88, 89, 90, 94, 48, 51,59, 60, 68, 74, 77, 84, 91, 93, 37, 54, 56, 58, 61, 70, 71, 85, 102,115, 124, 126, 72, 73, 75, 92, 96, 95, 99, 100, 104, 64, 65, 67, 76, 78,130, 131, 145, 162, 172, 193, 196 106, 125, 133, 105, 109, 110, 79, 81,82, 83, 97, 146, 152, 157, 135, 151, 156, 111, 112, 114, 98, 101, 107,108, 164, 167, 168, 186, 191, 194 117, 118, 119, 113, 116, 121, 169,189, 190, 120, 122, 129, 123, 127, 128, 195, 197 137, 141, 142, 132,134, 136, 143, 144, 150, 138, 139, 140, 154, 155, 160, 147, 148, 149,163, 170, 178, 153, 158, 159, 184, 188 161, 165, 166, 171, 175, 176,177, 179, 181, 182, 183, 185, 187, 192

Table 5 below describes inhibitory activity of compounds of Formula I onhuman P-glycoprotein HEK cells (HEK-P-gp) pretreated with elacridarwhere “+++++” indicates a measured IC₅₀ value <0.025 μM; “++++”indicates a measured IC₅₀ value from 0.025 μM to 0.050 μM of thedisclosed compound; “+++” indicates a measured IC₅₀ value from 0.050 μMto 0.10 μM of the disclosed compound; “++” indicates a measured IC₅₀value from 0.10 μM to 0.50 μM of the disclosed compound; and “+”indicates a measured IC₅₀ value >0.50 μM of the disclosed compound.

TABLE 5 Compounds with Compounds with Compounds with Compounds withCompounds with an IC₅₀ an IC₅₀ value from an IC₅₀ value from an IC₅₀value from an IC₅₀ value <0.025 μM 0.025 μM to 0.050 μM 0.050 μM to 0.10μM 0.10 μM to 0.50 μM value >0.50 μM 1, 8, 13, 15, 17, 18, 12, 20, 21,22, 27, 9, 16, 47, 48, 51, 52, 3, 7, 10, 24, 38, 39, 4, 5, 6, 11, 14,25, 19, 23, 29, 31, 32, 28, 30, 40, 50, 53, 66, 73, 75, 77, 78, 45, 46,54, 55, 56, 26, 37, 58, 61, 64, 33, 34, 35, 36, 41, 68, 80, 84, 87, 88,91, 93, 95, 96, 110, 74, 79, 97, 100, 104, 65, 67, 76, 81, 82, 42, 43,44, 49, 57, 90, 92, 106, 125, 117, 118, 119, 124, 105, 109, 111, 112,83, 98, 99, 101, 107, 59, 60, 62, 63, 69, 127, 129, 132, 163, 135, 151,158, 162, 114, 116, 120, 122, 108, 113, 121, 123, 70, 71, 72, 85, 86,172, 186 178, 186, 193, 194, 137, 138, 139, 142, 128, 134, 136, 140, 89,94, 102, 115, 195, 196, 197 143, 144, 147, 148, 141, 149, 153, 159, 126,130, 131, 133, 150, 154, 155, 160, 161, 165, 166, 171, 145, 146, 152,156, 170, 175, 179, 184, 176, 177, 181, 182, 157, 164, 167, 168, 188,191 183, 185, 187, 192 169, 172, 189, 190

Table 6 below describes half-maximal effective concentration (EC₅₀) ofcompounds of Formula I in the fetal hemoglobin (HbF) upregulation assayof HUDEP2 cells where “+++++” indicates a measured EC₅₀ value <0.025 μM;“++++” indicates a measured EC₅₀ value from 0.025 μM to 0.050 μM of thedisclosed compound; “+++” indicates a measured EC₅₀ value from 0.050 μMto 0.10 μM of the disclosed compound; “++” indicates a measured EC₅₀value from 0.10 μM to 0.50 μM of the disclosed compound; and “+”indicates a measured EC₅₀ value >0.50 μM of the disclosed compound.

TABLE 6 Compounds with Compounds with Compounds with Compounds with anEC₅₀ an EC₅₀ value from an EC₅₀ value from an EC₅₀ value from value<0.025 μM 0.025 μM to 0.050 μM 0.050 μM to 0.10 μM 0.10 μM to 0.50 μM17, 33, 71, 115 8, 28, 29, 31, 57, 69, 13, 18, 19, 36, 49 23, 30, 62 70,72, 184

Table 7 below describes half-maximal effective concentration (EC₅₀) ofcompounds of Formula I in the fetal hemoglobin (HbF) upregulation assayof CD34+ cells where “+++++” indicates a measured EC₅₀ value <0.025 μM;“++++” indicates a measured EC₅₀ value from 0.025 μM to 0.050 μM of thedisclosed compound; “+++” indicates a measured EC₅₀ value from 0.050 μMto 0.10 μM of the disclosed compound; “++” indicates a measured EC₅₀value from 0.10 μM to 0.50 μM of the disclosed compound; and “+”indicates a measured EC₅₀ value >0.50 μM of the disclosed compound.

TABLE 7 Compounds with Compounds with Compounds with an EC₅₀ an EC₅₀value from an EC₅₀ value from value <0.025 μM 0.050 μM to 0.10 μM 0.10μM to 0.50 μM 17, 131, 164 8, 18, 33, 57, 69, 70, 15, 20, 28, 85, 94 71,89, 115, 130, 146

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

What is claimed is:
 1. A compound having the formula Ih-a:

or a pharmaceutically acceptable salt thereof, wherein A₁ is —O—; A₂ is—CH₂—; R₂ and R₃ are each independently selected, for each occurrence,from the group consisting of: H, halogen, —OH, and Ci alkyl, wherein theCi alkyl is optionally substituted with one or more halogens; and R₁ isselected from the group consisting of:


2. The compound of claim 1, wherein R₁ is


3. The compound of claim 2, wherein R₂ is selected from the groupconsisting of H, C₁-C₆ alkyl, or halogen.
 4. A compound represented by:

or a pharmaceutically acceptable salt thereof.
 5. A compound representedby:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 7. A pharmaceutical composition comprising acompound of claim 5 and a pharmaceutically acceptable carrier.
 8. Apharmaceutical composition comprising a compound of claim 4 and apharmaceutically acceptable carrier.
 9. A method of treating a blooddisorder comprising administering to a subject in need thereof apharmaceutically effective amount of the compound of claim
 1. 10. Themethod of claim 9, wherein the blood disorder is selected from the groupconsisting of acute lymphoblastic leukemia (ALL), Acute myeloid leukemia(AML), Amyloidosis, Anemia, aplastic anemia, bone marrow failuresyndromes, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia(CML), deep vein thrombosis (DVT), Diamond-Blackfan anemia, diffusedlarge B cell lymphoma, dyskeratosis congenita (DKC), eosinophilicdisorder, essential thrombocythemia, Fanconi anemia, follicularlymphoma, Gaucher disease, hemochromatosis, hemolytic anemia,hemophilia, hereditary spherocytosis, Hodgkin's lymphoma, idiopathicthrombocytopenic purpura (ITP), inherited bone marrow failure syndromes,iron-deficiency anemia, Langerhans cell histiocytosis, large granularlymphocytic (LGL) leukemia, leukopenia, mastocytosis, monoclonalgammopathy, multiple myeloma, myelodysplastic syndromes (MDS),myelofibrosis, myeloproliferative neoplasms (MPN), Non-Hodgkin'slymphoma, paroxysmal nocturnal hemoglobinuria (PNH), polycythemia vera,porphyria, post-transplant lymphoproliferative disorder (PTLD),pulmonary embolism (PE), Shwachman-Diamond syndrome (SDS), sickle celldisease (SCD), β-thalassemia, thrombocytopenia, thromboticthrombocytopenic purpura (TTP), venous thromboembolism, Von Willebranddisease, and Waldenstrom's macroglobulinemia (lymphoplasmacyticlymphoma).
 11. The method of claim 10, wherein the blood disorder issickle cell disease (SCD).
 12. The method of claim 10, wherein the blooddisorder is β-thalassemia.
 13. A method of treating sickle cell diseaseor β-thalassemia, comprising administering to a subject in need thereofa therapeutically effective amount of the compound according to theformula:

or a pharmaceutically acceptable salt thereof.